{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Warburg Effect", "entry_form": "phenomenon", "gradeable_restatement": "Aerobic glycolysis is a primary causal driver of malignant transformation and sustained tumour growth rather than a metabolic consequence of upstream oncogenic signalling.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Species, genotype, baseline disease, diet, dose and timing", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Warburg Effect", "central_claim": "Aerobic glycolysis is a primary causal driver of malignant transformation and sustained tumour growth rather than a metabolic consequence of upstream oncogenic signalling.", "proposed_mechanism": "Aerobic glycolysis is a primary causal driver of malignant transformation and sustained tumour growth rather than a metabolic consequence of upstream oncogenic signalling.", "claimed_scope": "Malignant transformation and maintenance across tumour classes; initiation, established primary growth, metastasis and relapse are separated. Culture and engineered transplantation retain their own scopes.", "claimed_level": [ "initiation", "necessity", "primacy", "generalization" ], "is_conjunctive": true, "conjunctive_note": "The index designates primary-subclaim aggregation with SC3 gating primacy. The real metabolic observation SC1 cannot be labelled refuted because the stronger causal-driver claim fails." }, "rubric_routing": { "primary_rubric": "02-cancer-biology.md", "secondary_rubrics": [ "06-metabolism-aging.md" ], "index_notes_applied": [ "The index designates primary-subclaim aggregation with SC3 gating primacy. The real metabolic observation SC1 cannot be labelled refuted because the stronger causal-driver claim fails." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Many cancer cells exhibit preferential aerobic glycolysis.", "subclaim_type": "existence", "scope": "defined human and experimental tumour types", "claimed_scope": "defined human and experimental tumour types", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "In vivo flux measurements separating tumour/stroma and perfusion", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Human and mouse tracing confirms increased glycolytic activity in many tumours, alongside respiration and fuel heterogeneity. This descriptive existence claim is supported without a causal upgrade [33,49–56]." }, { "id": "SC2", "statement": "The aerobic glycolytic state is necessary for tumour growth.", "subclaim_type": "necessity", "scope": "defined endogenous tumours; cell culture scored separately", "claimed_scope": "defined endogenous tumours; cell culture scored separately", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Selective endogenous metabolic loss with tumour outcomes and orthogonal rescue", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Specific HK2 and other metabolic dependencies have positive endogenous causal tests, but the general aerobic fermentation state is not required in all assessed tumours. PKM2 isoform loss is not equivalent to removal of glycolysis; the LDHA SCC null more directly constrains fermentation necessity [44–48,65–67]." }, { "id": "SC3", "statement": "Aerobic glycolysis is a primary upstream driver rather than a consequence of oncogenic signalling.", "subclaim_type": "primacy", "scope": "malignant transformation and maintenance across tumour classes", "claimed_scope": "malignant transformation and maintenance across tumour classes", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Metabolic perturbation with oncogenic signalling intact, initiation/trajectory and epistasis", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Metabolic feedback can activate oncogenic signals in culture, but endogenous KRAS withdrawal, copy-number and effector tests generally place an oncogene before reprogramming. A general glycolysis-first transformation/maintenance model has not crossed its causal threshold [31,35,37–41,57,68]." } ], "aggregation_rule": "primary-subclaim", "aggregation_preregistered": true, "aggregation_rationale": "The index designates primary-subclaim aggregation with SC3 gating primacy. The real metabolic observation SC1 cannot be labelled refuted because the stronger causal-driver claim fails.", "primary_subclaim_id": "SC3", "aggregation_derivation": "Primary-subclaim SC3 returns Γ. Cell-level feedback and strong context-specific metabolic contributions make the hypothesis more than association, but no examined evidence set establishes general upstream metabolic primacy across tumour classes. SC2 remains Γ for the registered broad state-necessity claim; named endogenous dependencies reach Ε as a competing model. Weakest-link sensitivity is Β due to descriptive SC1; primary and scope-matched sensitivities are Γ. The real Warburg observation is not labelled refuted.", "aggregation_alternatives": { "weakest_link_would_return": "Β", "primary_subclaim_would_return": "Γ", "scope_matched_would_return": "Γ", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M2", "is_nominal": false, "name": "Oncogene-driven reprogramming with feedback", "core_claim": "Oncogenic lesions induce metabolic programs that subsequently support tumour behaviour.", "explains_what_nominal_does_not": "Oncogenic lesions induce metabolic programs that subsequently support tumour behaviour.", "strongest_supporting_evidence": [ "Inducible KRAS dependence, KRAS allele-dose progression, direct KRAS4A-HK1 interaction and KRAS-NIX/p38gamma effectors support directionality [31,35,39–41,57]." ], "strongest_contradictory_evidence": [ "Oncogenes are pleiotropic and metabolic feedback can also activate signalling; this is not an exclusively one-way model." ], "hsef_level_for_this_model": "Ε", "rationale": "Inducible KRAS dependence, KRAS allele-dose progression, direct KRAS4A-HK1 interaction and KRAS-NIX/p38gamma effectors support directionality [31,35,39–41,57]. Oncogenes are pleiotropic and metabolic feedback can also activate signalling; this is not an exclusively one-way model." }, { "rank_in_tournament": 2, "model_id": "M3", "is_nominal": false, "name": "Context-specific respiration and biosynthetic outputs", "core_claim": "Mitochondrial redox and aspartate/asparagine output can constrain proliferation and persistence.", "explains_what_nominal_does_not": "Mitochondrial redox and aspartate/asparagine output can constrain proliferation and persistence.", "strongest_supporting_evidence": [ "TFAM loss, aspartate rescue, engineered bypass and selected relapse-state dependencies narrow outputs and contexts [21–24,28,30,38]." ], "strongest_contradictory_evidence": [ "Respiration can be bypassed in cells or by environmental nutrients; aspartate was not limiting in every tumour [28]." ], "hsef_level_for_this_model": "Ε", "rationale": "TFAM loss, aspartate rescue, engineered bypass and selected relapse-state dependencies narrow outputs and contexts [21–24,28,30,38]. Respiration can be bypassed in cells or by environmental nutrients; aspartate was not limiting in every tumour [28]." }, { "rank_in_tournament": 3, "model_id": "M5", "is_nominal": false, "name": "Metabolic symbiosis and flexible fuel use", "core_claim": "Tumour compartments use lactate and other fuels according to oxygen, stage and nutrient access.", "explains_what_nominal_does_not": "Tumour compartments use lactate and other fuels according to oxygen, stage and nutrient access.", "strongest_supporting_evidence": [ "Human lactate tracing and mouse uptake loss identify a fuel route; endogenous SCC loss and double loss map compensation [49–51,58,66–67]." ], "strongest_contradictory_evidence": [ "Tracing proves use, not necessity; transporter inhibition has alternative effects and full human lineage-resolved dependence remains incomplete." ], "hsef_level_for_this_model": "Ε", "rationale": "Human lactate tracing and mouse uptake loss identify a fuel route; endogenous SCC loss and double loss map compensation [49–51,58,66–67]. Tracing proves use, not necessity; transporter inhibition has alternative effects and full human lineage-resolved dependence remains incomplete." }, { "rank_in_tournament": 4, "model_id": "M4", "is_nominal": false, "name": "Proliferation-related redox constraint", "core_claim": "NAD regeneration and shuttle capacity can cause lactate fermentation without a unique cancer-initiating role.", "explains_what_nominal_does_not": "NAD regeneration and shuttle capacity can cause lactate fermentation without a unique cancer-initiating role.", "strongest_supporting_evidence": [ "PDH/redox rescue and NADH-shuttle modulation separate fermentation rate from proliferation [63–64]." ], "strongest_contradictory_evidence": [ "The strongest direct tests are cultured cells; autochthonous long-term stage-specific generalization remains open." ], "hsef_level_for_this_model": "Γ", "rationale": "PDH/redox rescue and NADH-shuttle modulation separate fermentation rate from proliferation [63–64]. The strongest direct tests are cultured cells; autochthonous long-term stage-specific generalization remains open." }, { "rank_in_tournament": 5, "model_id": "M1", "is_nominal": true, "name": "Glycolysis as primary upstream driver", "core_claim": "Aerobic fermentation starts and generally maintains malignant state before oncogenic signalling.", "explains_what_nominal_does_not": "Aerobic fermentation starts and generally maintains malignant state before oncogenic signalling.", "strongest_supporting_evidence": [ "GLUT3 culture transformation, YAP feedback and named glycolytic dependencies are its strongest support [10–11,37,44,46]." ], "strongest_contradictory_evidence": [ "Overexpression, enzyme multifunctionality, endogenous fermentation nulls and oncogene-to-flux direction block full-scope primacy [45–48,57,64–67]." ], "hsef_level_for_this_model": "Γ", "rationale": "GLUT3 culture transformation, YAP feedback and named glycolytic dependencies are its strongest support [10–11,37,44,46]. Overexpression, enzyme multifunctionality, endogenous fermentation nulls and oncogene-to-flux direction block full-scope primacy [45–48,57,64–67]." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. The strongest separator is inducible KRAS maintenance control [57] versus GLUT3 culture sufficiency [37]. The endogenous HFSC SCC LDHA null [67], with reduced metabolic and FDG signals but preserved tumours, tests the nominated fermentation state more directly than PKM2 isoform deletion alone.", "study_separating_rank1_from_rank2": "The strongest separator is inducible KRAS maintenance control [57] versus GLUT3 culture sufficiency [37]. The endogenous HFSC SCC LDHA null [67], with reduced metabolic and FDG signals but preserved tumours, tests the nominated fermentation state more directly than PKM2 isoform deletion alone.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "38961290", "title": "NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance.", "citation": "Chen H, Li Y, Li H et al. NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance. Nature. 2024.", "doi": "10.1038/s41586-024-07620-9", "pmcid": "PMC11254748", "url": "https://pubmed.ncbi.nlm.nih.gov/38961290/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38961290/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID38961290", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "cancer models / human association", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "LDHA reduction and site-specific NBS1 lactylation work link lactate to DNA repair and chemotherapy resistance.", "what_it_does_not_show": "Resistance is distinct from initiation; the abstract's anaerobic wording does not redefine aerobic glycolysis as oxygen absence.", "confounders_present": [ "Resistance is distinct from initiation; the abstract's anaerobic wording does not redefine aerobic glycolysis as oxygen absence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 2, "pmid": "29455928", "title": "Transcriptional Regulation of the Warburg Effect in Cancer by SIX1.", "citation": "Li L, Liang Y, Kang L et al. Transcriptional Regulation of the Warburg Effect in Cancer by SIX1. Cancer cell. 2018.", "doi": "10.1016/j.ccell.2018.01.010", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29455928/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29455928/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID29455928", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cancer cells / in vivo models", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "SIX1 transcriptional regulation increased glycolytic genes and tumour growth.", "what_it_does_not_show": "A transcriptional driver upstream of metabolism does not establish glycolysis as the primary initiating event.", "confounders_present": [ "A transcriptional driver upstream of metabolism does not establish glycolysis as the primary initiating event." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 3, "pmid": "34921016", "title": "ASO-Based PKM Splice-Switching Therapy Inhibits Hepatocellular Carcinoma Growth.", "citation": "Ma WK, Voss DM, Scharner J et al. ASO-Based PKM Splice-Switching Therapy Inhibits Hepatocellular Carcinoma Growth. Cancer research. 2022.", "doi": "10.1158/0008-5472.CAN-20-0948", "pmcid": "PMC8898261", "url": "https://pubmed.ncbi.nlm.nih.gov/34921016/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34921016/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID34921016", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "HCC cells / genetic mouse HCC", "decisive_perturbation": true, "endogenous": true, "direction": "positive", "what_it_shows": "Independent splice-switching ASOs altered PKM isoforms and inhibited xenograft and genetic HCC tumourigenesis.", "what_it_does_not_show": "Splice replacement is not PKM2 deletion; genotype, increased pyruvate-kinase activity and nonmetabolic functions remain relevant.", "confounders_present": [ "Splice replacement is not PKM2 deletion; genotype, increased pyruvate-kinase activity and nonmetabolic functions remain relevant." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 4, "pmid": "35547764", "title": "mTOR regulates aerobic glycolysis through NEAT1 and nuclear paraspeckle-mediated mechanism in hepatocellular carcinoma.", "citation": "Zhang H, Su X, Burley SK et al. mTOR regulates aerobic glycolysis through NEAT1 and nuclear paraspeckle-mediated mechanism in hepatocellular carcinoma. Theranostics. 2022.", "doi": "10.7150/thno.72581", "pmcid": "PMC9065186", "url": "https://pubmed.ncbi.nlm.nih.gov/35547764/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35547764/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID35547764", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "HCC cells / AKT-NRAS mouse model", "decisive_perturbation": true, "endogenous": true, "direction": "positive", "what_it_shows": "mTOR-NEAT1-paraspeckle regulation controlled glycolytic splicing and tumour growth in an oncogene-driven model.", "what_it_does_not_show": "The initiating oncogene and broad RNA-processing changes precede the metabolic phenotype; selective flux mediation is not fully isolated.", "confounders_present": [ "The initiating oncogene and broad RNA-processing changes precede the metabolic phenotype; selective flux mediation is not fully isolated." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 5, "pmid": "35002506", "title": "HPV E6/E7 promotes aerobic glycolysis in cervical cancer by regulating IGF2BP2 to stabilize m6A-MYC expression.", "citation": "Hu C, Liu T, Han C et al. HPV E6/E7 promotes aerobic glycolysis in cervical cancer by regulating IGF2BP2 to stabilize m6A-MYC expression. International journal of biological sciences. 2022.", "doi": "10.7150/ijbs.67770", "pmcid": "PMC8741847", "url": "https://pubmed.ncbi.nlm.nih.gov/35002506/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35002506/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID35002506", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cervical cancer cells / in vivo", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "E6/E7 knockdown reduced glycolysis and growth, with IGF2BP2 rescue and MYC-linked regulation.", "what_it_does_not_show": "The viral oncogenes sit upstream and rescue affects RNA regulation broadly; this is not proof of glycolysis-first initiation.", "confounders_present": [ "The viral oncogenes sit upstream and rescue affects RNA regulation broadly; this is not proof of glycolysis-first initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 6, "pmid": "25394852", "title": "Glycolysis inhibitor 2-deoxy-D-glucose suppresses carcinogen-induced rat hepatocarcinogenesis by restricting cancer cell metabolism.", "citation": "Wang Z, Zhang L, Zhang D et al. Glycolysis inhibitor 2-deoxy-D-glucose suppresses carcinogen-induced rat hepatocarcinogenesis by restricting cancer cell metabolism. Molecular medicine reports. 2015.", "doi": "10.3892/mmr.2014.2945", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25394852/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25394852/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID25394852", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "DEN-induced rat HCC", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "2-DG delayed carcinogenesis and prolonged survival after DEN exposure.", "what_it_does_not_show": "2-DG affects multiple metabolic and glycosylation processes; DEN remains the initiating exposure and no selective metabolic rescue was presented in the abstract.", "confounders_present": [ "2-DG affects multiple metabolic and glycosylation processes; DEN remains the initiating exposure and no selective metabolic rescue was presented in the abstract." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 7, "pmid": "35802540", "title": "Detachment stress mediated bioenergetic switch of malignant melanoma cells into anti-Warburg phenotype.", "citation": "Uen W, Tseng T, Wu CP et al. Detachment stress mediated bioenergetic switch of malignant melanoma cells into anti-Warburg phenotype. Aging. 2022.", "doi": "10.18632/aging.204164", "pmcid": "PMC9320547", "url": "https://pubmed.ncbi.nlm.nih.gov/35802540/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35802540/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID35802540", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Weak", "system": "melanoma detachment cell model", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Detachment reduced lactate secretion and increased respiratory-inhibitor sensitivity.", "what_it_does_not_show": "Culture stress is not an endogenous metastatic lesion; adaptive oxidation challenges a fixed state without establishing universal respiration dependence.", "confounders_present": [ "Culture stress is not an endogenous metastatic lesion; adaptive oxidation challenges a fixed state without establishing universal respiration dependence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 8, "pmid": "39446384", "title": "O-GlcNAcylation of enolase 1 serves as a dual regulator of aerobic glycolysis and immune evasion in colorectal cancer.", "citation": "Zhu Q, Li J, Sun H et al. O-GlcNAcylation of enolase 1 serves as a dual regulator of aerobic glycolysis and immune evasion in colorectal cancer. Proceedings of the National Academy of Sciences of the United States of America. 2024.", "doi": "10.1073/pnas.2408354121", "pmcid": "PMC11536113", "url": "https://pubmed.ncbi.nlm.nih.gov/39446384/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39446384/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID39446384", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "colorectal cancer models", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Distinct ENO1 glycosylation sites regulated catalysis and PD-L1 stability, with tumour and immune effects.", "what_it_does_not_show": "One enzyme has separable metabolic and immune functions; site effects cannot all be attributed to glycolytic flux.", "confounders_present": [ "One enzyme has separable metabolic and immune functions; site effects cannot all be attributed to glycolytic flux." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 9, "pmid": "38286828", "title": "Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma.", "citation": "Mahmood M, Liu EM, Shergold AL et al. Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma. Nature cancer. 2024.", "doi": "10.1038/s43018-023-00721-w", "pmcid": "PMC11056318", "url": "https://pubmed.ncbi.nlm.nih.gov/38286828/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38286828/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID36993533" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID38286828", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph3. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "edited melanoma / patient association", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Mt-Nd5 truncation caused redox-linked glycolytic changes and enhanced checkpoint response in models.", "what_it_does_not_show": "A glycolytic shift can improve immune treatment response; isogenic cell growth was not substantially changed and human heteroplasmy response is observational.", "confounders_present": [ "A glycolytic shift can improve immune treatment response; isogenic cell growth was not substantially changed and human heteroplasmy response is observational." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 10, "pmid": "25796446", "title": "Aerobic glycolysis tunes YAP/TAZ transcriptional activity.", "citation": "Enzo E, Santinon G, Pocaterra A et al. Aerobic glycolysis tunes YAP/TAZ transcriptional activity. The EMBO journal. 2015.", "doi": "10.15252/embj.201490379", "pmcid": "PMC4491996", "url": "https://pubmed.ncbi.nlm.nih.gov/25796446/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25796446/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID25796446", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cells / Drosophila / human association", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Glycolytic perturbation modulated YAP/TAZ through PFK1-TEAD interaction and altered overgrowth in flies.", "what_it_does_not_show": "Feedback can reinforce oncogenic signalling but does not establish endogenous mammalian tumour initiation by flux alone.", "confounders_present": [ "Feedback can reinforce oncogenic signalling but does not establish endogenous mammalian tumour initiation by flux alone." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 11, "pmid": "18337823", "title": "The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth.", "citation": "Christofk HR, Vander Heiden MG, Harris MH et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008.", "doi": "10.1038/nature06734", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/18337823/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18337823/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID18337823", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "cancer-cell replacement / xenograft", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Replacing PKM2 with PKM1 reduced lactate, increased oxygen use and impaired xenograft formation.", "what_it_does_not_show": "Transplanted cell replacement does not establish endogenous PKM2 necessity or generalize to every tumour lineage.", "confounders_present": [ "Transplanted cell replacement does not establish endogenous PKM2 necessity or generalize to every tumour lineage." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 12, "pmid": "24140020", "title": "mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc.", "citation": "Masui K, Tanaka K, Akhavan D et al. mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc. Cell metabolism. 2013.", "doi": "10.1016/j.cmet.2013.09.013", "pmcid": "PMC3840163", "url": "https://pubmed.ncbi.nlm.nih.gov/24140020/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24140020/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID24140020", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "GBM signalling / patient association", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "mTORC2 regulated FoxO acetylation and MYC-linked glycolytic reprogramming.", "what_it_does_not_show": "Oncogenic signalling is upstream and patient survival correlations are not metabolic initiation evidence.", "confounders_present": [ "Oncogenic signalling is upstream and patient survival correlations are not metabolic initiation evidence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 13, "pmid": "31257027", "title": "BACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis.", "citation": "Wiel C, Le Gal K, Ibrahim MX et al. BACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis. Cell. 2019.", "doi": "10.1016/j.cell.2019.06.005", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31257027/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31257027/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID31257027", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "KRAS lung cancer / metastasis", "decisive_perturbation": true, "endogenous": true, "direction": "positive", "what_it_shows": "BACH1-linked glycolysis promoted antioxidant-associated metastasis and BACH1 targeting prevented that increase.", "what_it_does_not_show": "Metastatic amplification after KRAS-driven cancer is distinct from primary transformation and BACH1 has broader transcriptional functions.", "confounders_present": [ "Metastatic amplification after KRAS-driven cancer is distinct from primary transformation and BACH1 has broader transcriptional functions." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 14, "pmid": "21620138", "title": "Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1.", "citation": "Luo W, Hu H, Chang R et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 2011.", "doi": "10.1016/j.cell.2011.03.054", "pmcid": "PMC3130564", "url": "https://pubmed.ncbi.nlm.nih.gov/21620138/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21620138/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID21620138", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cancer cells / HIF feedback", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "PKM2-PHD3 interactions increased HIF coactivation and glycolytic flux.", "what_it_does_not_show": "PKM2 coactivation is a noncanonical enzyme function; loss of a regulator cannot isolate fermentation as the causal driver.", "confounders_present": [ "PKM2 coactivation is a noncanonical enzyme function; loss of a regulator cannot isolate fermentation as the causal driver." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 15, "pmid": "29533781", "title": "PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth.", "citation": "Morita M, Sato T, Nomura M et al. PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth. Cancer cell. 2018.", "doi": "10.1016/j.ccell.2018.02.004", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29533781/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29533781/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID29533781", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "PKM isoform mouse models / SCLC", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "PKM1 supported tumour growth in defined KRAS/carcinogen models and proliferation in pulmonary neuroendocrine cancers.", "what_it_does_not_show": "This counters PKM2-specific universality; active pyruvate kinase can support malignancy in particular lineages.", "confounders_present": [ "This counters PKM2-specific universality; active pyruvate kinase can support malignancy in particular lineages." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 16, "pmid": "25855294", "title": "SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance.", "citation": "Kim D, Fiske BP, Birsoy K et al. SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance. Nature. 2015.", "doi": "10.1038/nature14363", "pmcid": "PMC4533874", "url": "https://pubmed.ncbi.nlm.nih.gov/25855294/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25855294/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID25855294", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "glioma hypoxic regions / perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "SHMT2 lowered pyruvate-kinase activity and oxygen consumption, supporting survival in ischemic glioma regions.", "what_it_does_not_show": "Hypoxic survival adaptation differs from aerobic initiation; glycine toxicity and microenvironment shape the dependency.", "confounders_present": [ "Hypoxic survival adaptation differs from aerobic initiation; glycine toxicity and microenvironment shape the dependency." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 17, "pmid": "16809779", "title": "Cyclin D1 determines mitochondrial function in vivo.", "citation": "Sakamaki T, Casimiro MC, Ju X et al. Cyclin D1 determines mitochondrial function in vivo. Molecular and cellular biology. 2006.", "doi": "10.1128/MCB.02074-05", "pmcid": "PMC1592725", "url": "https://pubmed.ncbi.nlm.nih.gov/16809779/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16809779/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID16809779", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "mammary cyclin-D1 models", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Cyclin D1 perturbation reciprocally altered mitochondrial function and metabolic gene expression in mammary models.", "what_it_does_not_show": "Cell-cycle control and mitochondrial changes are coupled; the abstract does not isolate metabolic mediation of tumorigenesis.", "confounders_present": [ "Cell-cycle control and mitochondrial changes are coupled; the abstract does not isolate metabolic mediation of tumorigenesis." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 18, "pmid": "22052977", "title": "Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses.", "citation": "Anastasiou D, Poulogiannis G, Asara JM et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science (New York, N.Y.). 2011.", "doi": "10.1126/science.1211485", "pmcid": "PMC3471535", "url": "https://pubmed.ncbi.nlm.nih.gov/22052977/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22052977/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID22052977", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "lung cancer cells / xenograft", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Oxidation-resistant PKM2 reduced redox adaptation and impaired xenograft formation under oxidative stress.", "what_it_does_not_show": "PPP redox diversion is not equivalent to lactate dependence; transplanted growth retains the cancer-rubric scope cap.", "confounders_present": [ "PPP redox diversion is not equivalent to lactate dependence; transplanted growth retains the cancer-rubric scope cap." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 19, "pmid": "28054552", "title": "c-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis.", "citation": "Zhang J, Wang S, Jiang B et al. c-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis. Nature communications. 2017.", "doi": "10.1038/ncomms13732", "pmcid": "PMC5227066", "url": "https://pubmed.ncbi.nlm.nih.gov/28054552/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28054552/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID28054552", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "Src-HK cancer models", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Src phosphorylation activated HK1/HK2; phosphorylation-site mutation impaired growth and metastatic phenotypes.", "what_it_does_not_show": "Src is upstream, and low-glucose HK1 dependence limits claims of universal HK2 dependency.", "confounders_present": [ "Src is upstream, and low-glucose HK1 dependence limits claims of universal HK2 dependency." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 20, "pmid": "29892070", "title": "An inhibitor of oxidative phosphorylation exploits cancer vulnerability.", "citation": "Molina JR, Sun Y, Protopopova M et al. An inhibitor of oxidative phosphorylation exploits cancer vulnerability. Nature medicine. 2018.", "doi": "10.1038/s41591-018-0052-4", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29892070/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29892070/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID29892070", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "brain cancer and AML preclinical models", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "IACS-010759 inhibited OXPHOS-dependent tumour growth with energy and aspartate effects.", "what_it_does_not_show": "Preclinical therapeutic tolerability did not predict the subsequent human therapeutic window; respiration inhibition is not proof of glycolysis primacy.", "confounders_present": [ "Preclinical therapeutic tolerability did not predict the subsequent human therapeutic window; respiration inhibition is not proof of glycolysis primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 21, "pmid": "33609439", "title": "Asparagine couples mitochondrial respiration to ATF4 activity and tumor growth.", "citation": "Krall AS, Mullen PJ, Surjono F et al. Asparagine couples mitochondrial respiration to ATF4 activity and tumor growth. Cell metabolism. 2021.", "doi": "10.1016/j.cmet.2021.02.001", "pmcid": "PMC8102379", "url": "https://pubmed.ncbi.nlm.nih.gov/33609439/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33609439/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID33609439", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "ETC inhibition / mouse tumours", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Asparagine restored proliferation and signalling during respiratory impairment; combined restrictions impaired tumour growth.", "what_it_does_not_show": "Nutrient availability bypasses a respiratory output in defined contexts; no universal metabolic state is necessary in every tumour.", "confounders_present": [ "Nutrient availability bypasses a respiratory output in defined contexts; no universal metabolic state is necessary in every tumour." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 22, "pmid": "26232225", "title": "Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells.", "citation": "Sullivan LB, Gui DY, Hosios AM et al. Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. Cell. 2015.", "doi": "10.1016/j.cell.2015.07.017", "pmcid": "PMC4522278", "url": "https://pubmed.ncbi.nlm.nih.gov/26232225/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26232225/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID26232225", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "proliferating cell metabolic rescue", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Alternative electron acceptors or aspartate restored proliferation after respiratory-chain impairment.", "what_it_does_not_show": "Cell proliferation mechanistic rescue is strong within culture but not an endogenous tumour-initiation test.", "confounders_present": [ "Cell proliferation mechanistic rescue is strong within culture but not an endogenous tumour-initiation test." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 23, "pmid": "25241037", "title": "PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis.", "citation": "LeBleu VS, O'Connell JT, Gonzalez Herrera KN et al. PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nature cell biology. 2014.", "doi": "10.1038/ncb3039", "pmcid": "PMC4369153", "url": "https://pubmed.ncbi.nlm.nih.gov/25241037/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25241037/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID25241037", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "breast cancer invasion / in vivo metastasis", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "PGC-1alpha silencing reduced metastasis without reducing primary tumour growth, separating oxidative motility from proliferation.", "what_it_does_not_show": "Stage-specific effects are not universal respiration necessity. Linked erratum details were not fully audited.", "confounders_present": [ "Stage-specific effects are not universal respiration necessity. Linked erratum details were not fully audited." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 24, "pmid": "26232224", "title": "An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis.", "citation": "Birsoy K, Wang T, Chen WW et al. An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. Cell. 2015.", "doi": "10.1016/j.cell.2015.07.016", "pmcid": "PMC4522279", "url": "https://pubmed.ncbi.nlm.nih.gov/26232224/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26232224/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID26232224", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "cell CRISPR / aspartate rescue", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "GOT1-dependent aspartate production and supplementation explained proliferation rescue after ETC inhibition.", "what_it_does_not_show": "Cell metabolic outputs do not establish the general tumour-driver claim; supraphysiological supplementation and transporter expression matter.", "confounders_present": [ "Cell metabolic outputs do not establish the general tumour-driver claim; supraphysiological supplementation and transporter expression matter." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 25, "pmid": "28425994", "title": "Modulating the therapeutic response of tumours to dietary serine and glycine starvation.", "citation": "Maddocks ODK, Athineos D, Cheung EC et al. Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature. 2017.", "doi": "10.1038/nature22056", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28425994/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28425994/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID28770843" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID28425994", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "autochthonous Apc/Myc tumours", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Serine/glycine restriction improved survival in Apc and Myc models, with weaker responses in KRAS-driven cancers.", "what_it_does_not_show": "Dietary amino-acid dependence is genotype-specific and distinct from lactate fermentation; linked erratum is retained.", "confounders_present": [ "Dietary amino-acid dependence is genotype-specific and distinct from lactate fermentation; linked erratum is retained." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 26, "pmid": "39777474", "title": "Oxidative Phosphorylation Is a Metabolic Vulnerability of Endocrine Therapy-Tolerant Persister Cells in ER+ Breast Cancer.", "citation": "Tau S, Chamberlin MD, Yang H et al. Oxidative Phosphorylation Is a Metabolic Vulnerability of Endocrine Therapy-Tolerant Persister Cells in ER+ Breast Cancer. Cancer research. 2025.", "doi": "10.1158/0008-5472.CAN-24-1204", "pmcid": "PMC11908958", "url": "https://pubmed.ncbi.nlm.nih.gov/39777474/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39777474/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID39386444" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID39777474", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "ER+ persisters / patient specimens / xenograft", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Endocrine-tolerant persisters showed OXPHOS reliance; complex-I targeting suppressed tumour regrowth potential.", "what_it_does_not_show": "Human neoadjuvant specimens establish markers, not randomized OXPHOS inhibitor efficacy; persistence differs from initiation.", "confounders_present": [ "Human neoadjuvant specimens establish markers, not randomized OXPHOS inhibitor efficacy; persistence differs from initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 27, "pmid": "32210228", "title": "Subpopulation targeting of pyruvate dehydrogenase and GLUT1 decouples metabolic heterogeneity during collective cancer cell invasion.", "citation": "Commander R, Wei C, Sharma A et al. Subpopulation targeting of pyruvate dehydrogenase and GLUT1 decouples metabolic heterogeneity during collective cancer cell invasion. Nature communications. 2020.", "doi": "10.1038/s41467-020-15219-7", "pmcid": "PMC7093428", "url": "https://pubmed.ncbi.nlm.nih.gov/32210228/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32210228/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID32210228", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "collective invasion cell model", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Respiratory leaders and glucose-using followers required different metabolic interventions during collective invasion.", "what_it_does_not_show": "Subpopulation culture cooperation does not prove the same dependencies in intact human metastases.", "confounders_present": [ "Subpopulation culture cooperation does not prove the same dependencies in intact human metastases." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 28, "pmid": "29941931", "title": "Aspartate is an endogenous metabolic limitation for tumour growth.", "citation": "Sullivan LB, Luengo A, Danai LV et al. Aspartate is an endogenous metabolic limitation for tumour growth. Nature cell biology. 2018.", "doi": "10.1038/s41556-018-0125-0", "pmcid": "PMC6051729", "url": "https://pubmed.ncbi.nlm.nih.gov/29941931/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29941931/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID29941931", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Methods:paragraph1, 0:Methods:paragraph2, 0:Methods:paragraph11, 0:Methods:paragraph12, 2:Main text (unsectioned body paragraphs):paragraph6, 2:Main text (unsectioned body paragraphs):paragraph7, 2:Main text (unsectioned body paragraphs):paragraph8, 2:Main text (unsectioned body paragraphs):paragraph9, 2:Main text (unsectioned body paragraphs):paragraph10, 2:Main text (unsectioned body paragraphs):paragraph11, 2:Main text (unsectioned body paragraphs):paragraph12. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered aspartate bypass / transplanted tumours", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "gpASNase1 increased growth of selected transplanted tumours and bypassed metformin suppression; AsPC-1 growth did not increase.", "what_it_does_not_show": "Engineered enzyme sufficiency maps an endogenous nutrient limitation, not universal respiratory necessity or primary cancer initiation.", "confounders_present": [ "Engineered enzyme sufficiency maps an endogenous nutrient limitation, not universal respiratory necessity or primary cancer initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 29, "pmid": "33294863", "title": "Targeting Mitochondrial Complex I Overcomes Chemoresistance in High OXPHOS Pancreatic Cancer.", "citation": "Masoud R, Reyes-Castellanos G, Lac S et al. Targeting Mitochondrial Complex I Overcomes Chemoresistance in High OXPHOS Pancreatic Cancer. Cell reports. Medicine. 2020.", "doi": "10.1016/j.xcrm.2020.100143", "pmcid": "PMC7691450", "url": "https://pubmed.ncbi.nlm.nih.gov/33294863/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33294863/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID33294863", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "patient-derived PDAC / orthotopic models", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "High-OXPHOS PDAC subsets responded to phenformin plus gemcitabine in orthotopic models.", "what_it_does_not_show": "Clinical response was proposed rather than demonstrated; baseline tumour heterogeneity matters.", "confounders_present": [ "Clinical response was proposed rather than demonstrated; baseline tumour heterogeneity matters." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 30, "pmid": "25119024", "title": "Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function.", "citation": "Viale A, Pettazzoni P, Lyssiotis CA et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature. 2014.", "doi": "10.1038/nature13611", "pmcid": "PMC4376130", "url": "https://pubmed.ncbi.nlm.nih.gov/25119024/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25119024/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID41951747" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID25119024", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "inducible KRAS mouse PDAC", "decisive_perturbation": true, "endogenous": true, "direction": "positive", "what_it_shows": "Cells surviving KRAS ablation relied more on mitochondrial respiration and supported relapse.", "what_it_does_not_show": "A selected persistence state differs from untreated primary growth. A linked 2026 erratum is retained and its affected details were not audited.", "confounders_present": [ "A selected persistence state differs from untreated primary growth. A linked 2026 erratum is retained and its affected details were not audited." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 31, "pmid": "26909577", "title": "Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities.", "citation": "Kerr EM, Gaude E, Turrell FK et al. Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature. 2016.", "doi": "10.1038/nature16967", "pmcid": "PMC4780242", "url": "https://pubmed.ncbi.nlm.nih.gov/26909577/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26909577/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID26909577", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "KRAS-copy-number mouse lung cancer", "decisive_perturbation": true, "endogenous": true, "direction": "positive", "what_it_shows": "Endogenous mutant allele enrichment accompanied progression and a glycolytic/TCA/glutathione metabolic program.", "what_it_does_not_show": "Genotype precedes rewiring, and early versus advanced tumours differ; enrichment is not proof that metabolism independently initiated cancer.", "confounders_present": [ "Genotype precedes rewiring, and early versus advanced tumours differ; enrichment is not proof that metabolism independently initiated cancer." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 32, "pmid": "26541605", "title": "Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH.", "citation": "Yun J, Mullarky E, Lu C et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science (New York, N.Y.). 2015.", "doi": "10.1126/science.aaa5004", "pmcid": "PMC4778961", "url": "https://pubmed.ncbi.nlm.nih.gov/26541605/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26541605/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID26541605", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "CRC cells / Apc-KRAS mice", "decisive_perturbation": true, "endogenous": true, "direction": "positive", "what_it_shows": "High-dose vitamin C caused redox-linked GAPDH inhibition and impaired growth in Apc/KRAS mice.", "what_it_does_not_show": "Pleiotropic oxidative toxicity and genotype selection prevent treating this as a clean test of fermentation-only necessity or clinical efficacy.", "confounders_present": [ "Pleiotropic oxidative toxicity and genotype selection prevent treating this as a clean test of fermentation-only necessity or clinical efficacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 33, "pmid": "36725930", "title": "Slow TCA flux and ATP production in primary solid tumours but not metastases.", "citation": "Bartman CR, Weilandt DR, Shen Y et al. Slow TCA flux and ATP production in primary solid tumours but not metastases. Nature. 2023.", "doi": "10.1038/s41586-022-05661-6", "pmcid": "PMC10288502", "url": "https://pubmed.ncbi.nlm.nih.gov/36725930/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36725930/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID36725930", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse primary tumours and metastases", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Quantitative tracing found suppressed primary-solid-tumour TCA flux and calculated ATP synthesis, with higher TCA flux in metastases.", "what_it_does_not_show": "Calculated ATP depends on flux modelling assumptions; increased glycolysis did not imply greater total ATP production or a causal initiating lesion.", "confounders_present": [ "Calculated ATP depends on flux modelling assumptions; increased glycolysis did not imply greater total ATP production or a causal initiating lesion." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 34, "pmid": "27485932", "title": "Transformation by different oncogenes relies on specific metabolic adaptations.", "citation": "Peruzzo P, Comelli M, Di Giorgio E et al. Transformation by different oncogenes relies on specific metabolic adaptations. Cell cycle (Georgetown, Tex.). 2016.", "doi": "10.1080/15384101.2016.1215387", "pmcid": "PMC5053564", "url": "https://pubmed.ncbi.nlm.nih.gov/27485932/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27485932/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID27485932", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "oncogene-transformed fibroblasts", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "RAS and mutant HDAC4 produced different metabolic adaptations, with transformation without increased lactate in the latter.", "what_it_does_not_show": "In vitro engineered transformation does not establish every endogenous tumour route, but refutes a unique cell-model metabolic program.", "confounders_present": [ "In vitro engineered transformation does not establish every endogenous tumour route, but refutes a unique cell-model metabolic program." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 35, "pmid": "30819189", "title": "Obesogenic high-fat diet heightens aerobic glycolysis through hyperactivation of oncogenic KRAS.", "citation": "Wang D, Bi Y, Hu L et al. Obesogenic high-fat diet heightens aerobic glycolysis through hyperactivation of oncogenic KRAS. Cell communication and signaling : CCS. 2019.", "doi": "10.1186/s12964-019-0333-7", "pmcid": "PMC6396546", "url": "https://pubmed.ncbi.nlm.nih.gov/30819189/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30819189/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID30819189", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous KRAS-HFD pancreatic models", "decisive_perturbation": true, "endogenous": true, "direction": "positive", "what_it_shows": "COX2 deletion attenuated HFD-driven KRAS hyperactivation, glycolysis and dysplasia.", "what_it_does_not_show": "Diet, inflammation and oncogene activation are upstream; COX2 perturbation is not selective glycolytic subtraction.", "confounders_present": [ "Diet, inflammation and oncogene activation are upstream; COX2 perturbation is not selective glycolytic subtraction." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 36, "pmid": "19556508", "title": "Mitochondrial STAT3 supports Ras-dependent oncogenic transformation.", "citation": "Gough DJ, Corlett A, Schlessinger K et al. Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science (New York, N.Y.). 2009.", "doi": "10.1126/science.1171721", "pmcid": "PMC2840701", "url": "https://pubmed.ncbi.nlm.nih.gov/19556508/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19556508/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID19556508", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "RAS cell transformation / mitochondrial STAT3", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Mitochondria-targeted STAT3 mutants supported RAS transformation without canonical nuclear signalling.", "what_it_does_not_show": "Engineered protein localization narrows a mitochondrial contribution rather than universal upstream glycolytic causation.", "confounders_present": [ "Engineered protein localization narrows a mitochondrial contribution rather than universal upstream glycolytic causation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 37, "pmid": "24316969", "title": "Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways.", "citation": "Onodera Y, Nam JM, Bissell MJ et al. Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways. The Journal of clinical investigation. 2014.", "doi": "10.1172/JCI63146", "pmcid": "PMC3871217", "url": "https://pubmed.ncbi.nlm.nih.gov/24316969/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24316969/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID24316969", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "3D human breast-cell culture", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "GLUT3 overexpression increased glucose uptake and activated oncogenic signalling and disorganized architecture; reduced uptake restored polarity.", "what_it_does_not_show": "Overexpression and tissue architecture are not endogenous incidence or proof of aerobic lactate flux as sufficient primary cause.", "confounders_present": [ "Overexpression and tissue architecture are not endogenous incidence or proof of aerobic lactate flux as sufficient primary cause." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 38, "pmid": "20421486", "title": "Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity.", "citation": "Weinberg F, Hamanaka R, Wheaton WW et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proceedings of the National Academy of Sciences of the United States of America. 2010.", "doi": "10.1073/pnas.1003428107", "pmcid": "PMC2889315", "url": "https://pubmed.ncbi.nlm.nih.gov/20421486/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20421486/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID20421486", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "KRAS cells / TFAM mouse lung model", "decisive_perturbation": true, "endogenous": true, "direction": "positive", "what_it_shows": "TFAM loss reduced KRAS-driven tumorigenesis; mitochondrial ROS and glutamine metabolism supported transformation.", "what_it_does_not_show": "Mitochondrial output necessity in this model contradicts a simple defective-respiration account without making it universal.", "confounders_present": [ "Mitochondrial output necessity in this model contradicts a simple defective-respiration account without making it universal." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 39, "pmid": "31827279", "title": "KRAS4A directly regulates hexokinase 1.", "citation": "Amendola CR, Mahaffey JP, Parker SJ et al. KRAS4A directly regulates hexokinase 1. Nature. 2019.", "doi": "10.1038/s41586-019-1832-9", "pmcid": "PMC6923592", "url": "https://pubmed.ncbi.nlm.nih.gov/31827279/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31827279/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID31827279", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "KRAS4A-HK1 biochemistry / cells", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "GTP-dependent KRAS4A binding directly regulated HK1, providing an oncogene-to-metabolic-enzyme link.", "what_it_does_not_show": "Direct binding is not itself an endogenous tumour-survival intervention or complete clinical mechanism.", "confounders_present": [ "Direct binding is not itself an endogenous tumour-survival intervention or complete clinical mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 40, "pmid": "31263025", "title": "Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer.", "citation": "Humpton TJ, Alagesan B, DeNicola GM et al. Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer. Cancer discovery. 2019.", "doi": "10.1158/2159-8290.CD-18-1409", "pmcid": "PMC6726540", "url": "https://pubmed.ncbi.nlm.nih.gov/31263025/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31263025/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID31263025", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "KPC pancreatic genetic model", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Nix loss delayed PDAC progression and improved survival, while later mitochondrial-clearance compensation allowed progression.", "what_it_does_not_show": "The KRAS-NIX program is upstream of altered flux; delay is not permanent abrogation or generic metabolic sufficiency.", "confounders_present": [ "The KRAS-NIX program is upstream of altered flux; delay is not permanent abrogation or generic metabolic sufficiency." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 41, "pmid": "32580961", "title": "p38γ MAPK Is Essential for Aerobic Glycolysis and Pancreatic Tumorigenesis.", "citation": "Wang F, Qi XM, Wertz R et al. p38γ MAPK Is Essential for Aerobic Glycolysis and Pancreatic Tumorigenesis. Cancer research. 2020.", "doi": "10.1158/0008-5472.CAN-19-3281", "pmcid": "PMC9358694", "url": "https://pubmed.ncbi.nlm.nih.gov/32580961/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32580961/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID39957350" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID32580961", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "KPC pancreatic genetic model", "decisive_perturbation": true, "endogenous": true, "direction": "positive", "what_it_shows": "Pancreatic p38gamma loss reduced glycolytic intermediates/signalling and PDAC, with PFKFB3 pathway epistasis.", "what_it_does_not_show": "The kinase has broader signalling roles and sits downstream of KRAS. Linked erratum PMID39957350 limits unaudited details.", "confounders_present": [ "The kinase has broader signalling roles and sits downstream of KRAS. Linked erratum PMID39957350 limits unaudited details." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 42, "pmid": "22922757", "title": "Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis.", "citation": "Anastasiou D, Yu Y, Israelsen WJ et al. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nature chemical biology. 2012.", "doi": "10.1038/nchembio.1060", "pmcid": "PMC3711671", "url": "https://pubmed.ncbi.nlm.nih.gov/22922757/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22922757/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID22922757", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "PKM2 activation / xenograft", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "PKM2 activators promoted an active tetramer and reduced xenograft growth.", "what_it_does_not_show": "Activity modulation differs from deletion and from PKM1 expression in every lineage; linked correction details were not fully audited.", "confounders_present": [ "Activity modulation differs from deletion and from PKM1 expression in every lineage; linked correction details were not fully audited." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 43, "pmid": "25482511", "title": "Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation.", "citation": "Lunt SY, Muralidhar V, Hosios AM et al. Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation. Molecular cell. 2015.", "doi": "10.1016/j.molcel.2014.10.027", "pmcid": "PMC4289430", "url": "https://pubmed.ncbi.nlm.nih.gov/25482511/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25482511/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID25482511", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "primary nontransformed cells", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "PKM1 expression after PKM2 deletion limited nucleotide synthesis; thymine rescued proliferation.", "what_it_does_not_show": "This is normal-cell proliferation, a specificity control rather than a cancer-initiating mechanism.", "confounders_present": [ "This is normal-cell proliferation, a specificity control rather than a cancer-initiating mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 44, "pmid": "29386513", "title": "Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin.", "citation": "DeWaal D, Nogueira V, Terry AR et al. Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nature communications. 2018.", "doi": "10.1038/s41467-017-02733-4", "pmcid": "PMC5792493", "url": "https://pubmed.ncbi.nlm.nih.gov/29386513/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29386513/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID29946147" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID29386513", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph4, 1:Results:paragraph5. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "DEN-HCC genetics / human-cell rescue", "decisive_perturbation": true, "endogenous": true, "direction": "positive", "what_it_shows": "Liver HK2 deletion reduced tumour incidence; WT but not kinase-dead or mitochondrial-binding-deficient HK2 restored cell phenotypes.", "what_it_does_not_show": "Both catalysis and mitochondrial binding were required in the rescue. Reduced glycolysis coexisted with maintained TCA flux; linked correction retained.", "confounders_present": [ "Both catalysis and mitochondrial binding were required in the rescue. Reduced glycolysis coexisted with maintained TCA flux; linked correction retained." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 45, "pmid": "29214019", "title": "PKM2 is not required for colon cancer initiated by APC loss.", "citation": "Lau AN, Israelsen WJ, Roper J et al. PKM2 is not required for colon cancer initiated by APC loss. Cancer & metabolism. 2017.", "doi": "10.1186/s40170-017-0172-1", "pmcid": "PMC5707917", "url": "https://pubmed.ncbi.nlm.nih.gov/29214019/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29214019/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID29214019", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph2, 1:Results:paragraph3. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "autochthonous Apc-loss colon cancer", "decisive_perturbation": false, "endogenous": false, "direction": "negative", "what_it_shows": "PKM2 deletion left tumour incidence, multiplicity, survival and nuclear beta-catenin unchanged despite confirmed recombination.", "what_it_does_not_show": "PKM2 loss is not removal of all glycolysis; PKM1 compensation and lineage boundaries remain explicit.", "confounders_present": [ "PKM2 loss is not removal of all glycolysis; PKM1 compensation and lineage boundaries remain explicit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 46, "pmid": "23911236", "title": "Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer.", "citation": "Patra KC, Wang Q, Bhaskar PT et al. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer cell. 2013.", "doi": "10.1016/j.ccr.2013.06.014", "pmcid": "PMC3753022", "url": "https://pubmed.ncbi.nlm.nih.gov/23911236/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23911236/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID23911236", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "autochthonous KRAS lung / ErbB2 mammary models", "decisive_perturbation": true, "endogenous": true, "direction": "positive", "what_it_shows": "HK2 deletion reduced initiation and maintenance despite HK1 expression, and systemic deletion was therapeutic in mice.", "what_it_does_not_show": "A first glucose-phosphorylation step supports multiple branches and enzyme functions; this does not prove primary fermentation initiation. Linked correction retained.", "confounders_present": [ "A first glucose-phosphorylation step supports multiple branches and enzyme functions; this does not prove primary fermentation initiation. Linked correction retained." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 47, "pmid": "24120138", "title": "PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells.", "citation": "Israelsen WJ, Dayton TL, Davidson SM et al. PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell. 2013.", "doi": "10.1016/j.cell.2013.09.025", "pmcid": "PMC3850755", "url": "https://pubmed.ncbi.nlm.nih.gov/24120138/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24120138/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID24120138", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "autochthonous Brca1-loss mammary model", "decisive_perturbation": false, "endogenous": false, "direction": "negative", "what_it_shows": "PKM2 loss accelerated mammary tumour formation, with heterogeneous PKM1 expression and proliferating PKM2-null cells.", "what_it_does_not_show": "An isoform-specific null is a strong boundary, not proof that tumours have no glucose-metabolism requirement.", "confounders_present": [ "An isoform-specific null is a strong boundary, not proof that tumours have no glucose-metabolism requirement." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 48, "pmid": "29854399", "title": "Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma.", "citation": "Dayton TL, Gocheva V, Miller KM et al. Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma. Cancer & metabolism. 2018.", "doi": "10.1186/s40170-018-0179-2", "pmcid": "PMC5977456", "url": "https://pubmed.ncbi.nlm.nih.gov/29854399/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29854399/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID29854399", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph11, 2:Results:paragraph12, 2:Results:paragraph14, 1:Methods:paragraph9, 2:Results:paragraph2, 2:Results:paragraph3, 2:Results:paragraph6. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "autochthonous KRAS-p53 sarcoma", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "PKM2 loss delayed onset but tumours eventually grew; lineage reporting assigned residual PKM2 to stroma and showed PKM1-positive proliferation.", "what_it_does_not_show": "Facilitated initiation is distinct from maintenance necessity; bulk expression mixes tumour and stromal compartments.", "confounders_present": [ "Facilitated initiation is distinct from maintenance necessity; bulk expression mixes tumour and stromal compartments." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 49, "pmid": "28985563", "title": "Lactate Metabolism in Human Lung Tumors.", "citation": "Faubert B, Li KY, Cai L et al. Lactate Metabolism in Human Lung Tumors. Cell. 2017.", "doi": "10.1016/j.cell.2017.09.019", "pmcid": "PMC5684706", "url": "https://pubmed.ncbi.nlm.nih.gov/28985563/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28985563/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "DALLAS-NSCLC-LACTATE-2017-cohort-overlap-unresolved", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "human lung isotope tracing / mouse transporter loss", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Human lactate infusion labelled tumour TCA intermediates; MCT1 loss in mouse tumours removed lactate-dependent labelling.", "what_it_does_not_show": "Fuel tracing and uptake loss are not proof that lactate oxidation is universally required for growth.", "confounders_present": [ "Fuel tracing and uptake loss are not proof that lactate oxidation is universally required for growth." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 50, "pmid": "26853473", "title": "Metabolic Heterogeneity in Human Lung Tumors.", "citation": "Hensley CT, Faubert B, Yuan Q et al. Metabolic Heterogeneity in Human Lung Tumors. Cell. 2016.", "doi": "10.1016/j.cell.2015.12.034", "pmcid": "PMC4752889", "url": "https://pubmed.ncbi.nlm.nih.gov/26853473/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26853473/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "DALLAS-NSCLC-TRACING-2016-cohort-overlap-unresolved", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Strong", "system": "human lung intraoperative tracing", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Tumours showed glycolysis and glucose oxidation with region-dependent use of additional nutrients.", "what_it_does_not_show": "Small surgical cohort and tissue heterogeneity limit extrapolation; flux coexistence is not an initiation experiment.", "confounders_present": [ "Small surgical cohort and tissue heterogeneity limit extrapolation; flux coexistence is not an initiation experiment." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 51, "pmid": "29045397", "title": "Glucose feeds the TCA cycle via circulating lactate.", "citation": "Hui S, Ghergurovich JM, Morscher RJ et al. Glucose feeds the TCA cycle via circulating lactate. Nature. 2017.", "doi": "10.1038/nature24057", "pmcid": "PMC5898814", "url": "https://pubmed.ncbi.nlm.nih.gov/29045397/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29045397/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID29045397", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse nutrient tracing / genetic tumours", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Circulating lactate supplied TCA carbon in tissues and lung/pancreatic tumours, sometimes exceeding direct glucose contribution.", "what_it_does_not_show": "Tracer contribution depends on feeding state and exchange; label incorporation does not alone establish growth necessity.", "confounders_present": [ "Tracer contribution depends on feeding state and exchange; label incorporation does not alone establish growth necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 52, "pmid": "25525878", "title": "Acetate is a bioenergetic substrate for human glioblastoma and brain metastases.", "citation": "Mashimo T, Pichumani K, Vemireddy V et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell. 2014.", "doi": "10.1016/j.cell.2014.11.025", "pmcid": "PMC4374602", "url": "https://pubmed.ncbi.nlm.nih.gov/25525878/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25525878/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID25525878", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Strong", "system": "human and orthotopic brain-tumour tracing", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Brain tumours oxidized acetate and glucose, with human acetate oxidation linked to ACSS2 expression.", "what_it_does_not_show": "Substrate use is observed rather than selectively required; orthotopic models and human samples have distinct access limits.", "confounders_present": [ "Substrate use is observed rather than selectively required; orthotopic models and human samples have distinct access limits." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 53, "pmid": "31811141", "title": "Reactive metabolite production is a targetable liability of glycolytic metabolism in lung cancer.", "citation": "Luengo A, Abbott KL, Davidson SM et al. Reactive metabolite production is a targetable liability of glycolytic metabolism in lung cancer. Nature communications. 2019.", "doi": "10.1038/s41467-019-13419-4", "pmcid": "PMC6898239", "url": "https://pubmed.ncbi.nlm.nih.gov/31811141/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31811141/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID31811141", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human/mouse NSCLC / Glo1 loss", "decisive_perturbation": true, "endogenous": false, "direction": "positive", "what_it_shows": "Glo1 ablation increased reactive-metabolite sensitivity and reduced mouse tumour growth.", "what_it_does_not_show": "Detoxification of a glycolytic byproduct is a consequence vulnerability, not proof of glycolysis-first oncogenesis.", "confounders_present": [ "Detoxification of a glycolytic byproduct is a consequence vulnerability, not proof of glycolysis-first oncogenesis." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 54, "pmid": "31846640", "title": "Does Tumor FDG-PET Avidity Represent Enhanced Glycolytic Metabolism in Non-Small Cell Lung Cancer?", "citation": "Kernstine KH, Faubert B, Do QN et al. Does Tumor FDG-PET Avidity Represent Enhanced Glycolytic Metabolism in Non-Small Cell Lung Cancer? The Annals of thoracic surgery. 2020.", "doi": "10.1016/j.athoracsur.2019.10.061", "pmcid": "PMC7370816", "url": "https://pubmed.ncbi.nlm.nih.gov/31846640/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31846640/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "DALLAS-NSCLC-FDG-2020-cohort-overlap-unresolved", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Strong", "system": "human NSCLC glucose tracing", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "FDG SUV did not correlate with glycolytic intermediate labelling and instead related to other respiratory substrate markers and proliferation.", "what_it_does_not_show": "FDG uptake cannot stand in for measured lactate fermentation or metabolic causal dependence.", "confounders_present": [ "FDG uptake cannot stand in for measured lactate fermentation or metabolic causal dependence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 55, "pmid": "22419606", "title": "Metabolism of [U-13 C]glucose in human brain tumors in vivo.", "citation": "Maher EA, Marin-Valencia I, Bachoo RM et al. Metabolism of [U-13 C]glucose in human brain tumors in vivo. NMR in biomedicine. 2012.", "doi": "10.1002/nbm.2794", "pmcid": "PMC3406255", "url": "https://pubmed.ncbi.nlm.nih.gov/22419606/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22419606/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID22419606", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Strong", "system": "human brain intraoperative tracing", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Glucose carbon entered lactate, TCA metabolism, anaplerosis and biosynthetic pools in human brain tumours.", "what_it_does_not_show": "Multiple carbon fates contradict a simple fermentation-only picture without measuring causal necessity.", "confounders_present": [ "Multiple carbon fates contradict a simple fermentation-only picture without measuring causal necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 56, "pmid": "22682223", "title": "Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo.", "citation": "Marin-Valencia I, Yang C, Mashimo T et al. Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo. Cell metabolism. 2012.", "doi": "10.1016/j.cmet.2012.05.001", "pmcid": "PMC3372870", "url": "https://pubmed.ncbi.nlm.nih.gov/22682223/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22682223/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID22682223", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "orthotopic patient-derived GBM tracing", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Three genetically distinct orthotopic GBM lines oxidized glucose and used it for biosynthesis.", "what_it_does_not_show": "Patient-derived graft metabolism does not substitute for selective endogenous loss; linked correction retained.", "confounders_present": [ "Patient-derived graft metabolism does not substitute for selective endogenous loss; linked correction retained." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 57, "pmid": "22541435", "title": "Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism.", "citation": "Ying H, Kimmelman AC, Lyssiotis CA et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell. 2012.", "doi": "10.1016/j.cell.2012.01.058", "pmcid": "PMC3472002", "url": "https://pubmed.ncbi.nlm.nih.gov/22541435/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22541435/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID22541435", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "inducible KRAS native PDAC", "decisive_perturbation": true, "endogenous": true, "direction": "positive", "what_it_shows": "KRAS withdrawal established maintenance dependence and controlled glucose routing into anabolic pathways.", "what_it_does_not_show": "This places a driver oncogene upstream; metabolic branches and KRAS pleiotropy are not isolated by withdrawal alone.", "confounders_present": [ "This places a driver oncogene upstream; metabolic branches and KRAS pleiotropy are not isolated by withdrawal alone." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 58, "pmid": "19033663", "title": "Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice.", "citation": "Sonveaux P, Végran F, Schroeder T et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. The Journal of clinical investigation. 2008.", "doi": "10.1172/JCI36843", "pmcid": "PMC2582933", "url": "https://pubmed.ncbi.nlm.nih.gov/19033663/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19033663/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID19033663", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "lactate transport / mouse tumour models", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "MCT1 targeting shifted oxidative cells toward glucose use, retarded tumour growth and altered hypoxic-cell survival.", "what_it_does_not_show": "Drug selectivity and microenvironmental nutrient competition limit a universal lactate/fermentation interpretation.", "confounders_present": [ "Drug selectivity and microenvironmental nutrient competition limit a universal lactate/fermentation interpretation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 59, "pmid": "16766262", "title": "Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance.", "citation": "Fantin VR, St-Pierre J, Leder P et al. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer cell. 2006.", "doi": "10.1016/j.ccr.2006.04.023", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16766262/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16766262/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID16766262", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "LDHA knockdown / tumour-cell complementation", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "LDHA reduction impaired tumourigenicity and human LDHA complementation reversed the phenotype.", "what_it_does_not_show": "Transplantation-linked maintenance is not universal endogenous initiation; oxygen and rescue specificity matter and correction retained.", "confounders_present": [ "Transplantation-linked maintenance is not universal endogenous initiation; oxygen and rescue specificity matter and correction retained." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 60, "pmid": "36658425", "title": "Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials.", "citation": "Yap TA, Daver N, Mahendra M et al. Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials. Nature medicine. 2023.", "doi": "10.1038/s41591-022-02103-8", "pmcid": "PMC11975418", "url": "https://pubmed.ncbi.nlm.nih.gov/36658425/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36658425/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID36658425", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "human phase-I trials", "decisive_perturbation": false, "endogenous": false, "direction": "negative", "what_it_shows": "IACS-010759 trials could not establish a recommended phase-II dose because target exposure was limited by lactate elevation and neurotoxicity, with limited activity.", "what_it_does_not_show": "Dose-limited pharmacology does not refute biological OXPHOS dependence; clinical safety and mechanistic validity are separate.", "confounders_present": [ "Dose-limited pharmacology does not refute biological OXPHOS dependence; clinical safety and mechanistic validity are separate." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 61, "pmid": "20463368", "title": "Metabolic modulation of glioblastoma with dichloroacetate.", "citation": "Michelakis ED, Sutendra G, Dromparis P et al. Metabolic modulation of glioblastoma with dichloroacetate. Science translational medicine. 2010.", "doi": "10.1126/scitranslmed.3000677", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/20463368/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20463368/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID20463368", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Weak", "system": "human GBM tissue / uncontrolled treatment", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "DCA altered mitochondrial signals in patient tissue and a small treated cohort, with reversible neuropathy limiting dose.", "what_it_does_not_show": "No randomized control or reliable efficacy estimate; biomarker change and clinical indications cannot establish cancer primacy.", "confounders_present": [ "No randomized control or reliable efficacy estimate; biomarker change and clinical indications cannot establish cancer primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 62, "pmid": "34407971", "title": "Recurrent Human Papillomavirus-Related Head and Neck Cancer Undergoes Metabolic Reprogramming and Is Driven by Oxidative Phosphorylation.", "citation": "Vyas A, Harbison RA, Faden DL et al. Recurrent Human Papillomavirus-Related Head and Neck Cancer Undergoes Metabolic Reprogramming and Is Driven by Oxidative Phosphorylation. Clinical cancer research : an official journal of the American Association for Cancer Research. 2021.", "doi": "10.1158/1078-0432.CCR-20-4789", "pmcid": "PMC8611487", "url": "https://pubmed.ncbi.nlm.nih.gov/34407971/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34407971/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID34407971", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "paired HPV-HNSCC / xenograft", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Recurrent cancers showed OXPHOS enrichment and NRF2-related respiratory vulnerability in experimental models.", "what_it_does_not_show": "Matched recurrence associations and xenograft inhibition do not show universal dependency or randomized clinical benefit.", "confounders_present": [ "Matched recurrence associations and xenograft inhibition do not show universal dependency or randomized clinical benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 63, "pmid": "33382985", "title": "Increased demand for NAD+ relative to ATP drives aerobic glycolysis.", "citation": "Luengo A, Li Z, Gui DY et al. Increased demand for NAD+ relative to ATP drives aerobic glycolysis. Molecular cell. 2021.", "doi": "10.1016/j.molcel.2020.12.012", "pmcid": "PMC8315838", "url": "https://pubmed.ncbi.nlm.nih.gov/33382985/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33382985/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID33382985", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "proliferating-cell PDH/redox rescue", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "PDH activation reduced NAD+/NADH and proliferation; uncoupling or ATP hydrolysis rescued both despite increased glucose oxidation.", "what_it_does_not_show": "A redox/ATP-demand mechanism in cells is not an endogenous cancer-initiation study.", "confounders_present": [ "A redox/ATP-demand mechanism in cells is not an endogenous cancer-initiation study." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 64, "pmid": "35973426", "title": "Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells.", "citation": "Wang Y, Stancliffe E, Fowle-Grider R et al. Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells. Molecular cell. 2022.", "doi": "10.1016/j.molcel.2022.07.007", "pmcid": "PMC10134440", "url": "https://pubmed.ncbi.nlm.nih.gov/35973426/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35973426/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID35973426", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "cell NADH-shuttle manipulation", "decisive_perturbation": false, "endogenous": false, "direction": "negative", "what_it_shows": "Increasing NADH-shuttle flux reduced lactate fermentation without reducing proliferation; fermentation correlated with shuttle capacity rather than growth.", "what_it_does_not_show": "Short-term cell behaviour and engineered shuttle activity cannot establish long-term tumour-wide dispensability.", "confounders_present": [ "Short-term cell behaviour and engineered shuttle activity cannot establish long-term tumour-wide dispensability." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 65, "pmid": "30209241", "title": "Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival.", "citation": "Pathria G, Scott DA, Feng Y et al. Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival. The EMBO journal. 2018.", "doi": "10.15252/embj.201899735", "pmcid": "PMC6187221", "url": "https://pubmed.ncbi.nlm.nih.gov/30209241/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30209241/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID30209241", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "melanoma LDHA inhibition / tumour models", "decisive_perturbation": false, "endogenous": false, "direction": "negative", "what_it_shows": "LDHA inhibition failed to impair melanoma proliferation or tumour growth and activated GCN2-ATF4/glutamine survival programs.", "what_it_does_not_show": "An effective adaptive bypass is actual dependency failure under that intervention; synthetic cotargeting does not restore LDHA-only necessity.", "confounders_present": [ "An effective adaptive bypass is actual dependency failure under that intervention; synthetic cotargeting does not restore LDHA-only necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 66, "pmid": "39303037", "title": "Defining metabolic flexibility in hair follicle stem cell induced squamous cell carcinoma.", "citation": "Galvan C, Flores AA, Cerrilos V et al. Defining metabolic flexibility in hair follicle stem cell induced squamous cell carcinoma. Science advances. 2024.", "doi": "10.1126/sciadv.adn2806", "pmcid": "PMC11414736", "url": "https://pubmed.ncbi.nlm.nih.gov/39303037/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39303037/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID37905122" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "HFSC-SCC-FLEXIBILITY-2024-journal", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph2, 1:RESULTS:paragraph6, 1:RESULTS:paragraph7, 2:DISCUSSION:paragraph0, 2:DISCUSSION:paragraph2, 2:DISCUSSION:paragraph3, 3:MATERIALS AND METHODS:paragraph1. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "HFSC SCC endogenous deletions", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "GLS loss alone preserved tumourigenesis with lactate-use compensation; combined LDHA/GLS loss prevented papilloma and carcinoma.", "what_it_does_not_show": "A joint-pathway requirement maps flexibility, not necessity of either individual pathway. Preprint and journal report are one study family.", "confounders_present": [ "A joint-pathway requirement maps flexibility, not necessity of either individual pathway. Preprint and journal report are one study family." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 67, "pmid": "30626875", "title": "Increased lactate dehydrogenase activity is dispensable in squamous carcinoma cells of origin.", "citation": "Flores A, Sandoval-Gonzalez S, Takahashi R et al. Increased lactate dehydrogenase activity is dispensable in squamous carcinoma cells of origin. Nature communications. 2019.", "doi": "10.1038/s41467-018-07857-9", "pmcid": "PMC6327029", "url": "https://pubmed.ncbi.nlm.nih.gov/30626875/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30626875/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID30914644" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "HFSC-SCC-LDHA-2019", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph4, 1:Results:paragraph5, 1:Results:paragraph6. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "HFSC SCC genetic and chemical models", "decisive_perturbation": false, "endogenous": false, "direction": "negative", "what_it_shows": "LDHA abrogation or induction did not alter tested tumour outcomes despite reduced glycolytic metabolites and FDG uptake.", "what_it_does_not_show": "Targeted fermentation is not all glucose metabolism. Multiple Cre/chemical paradigms strengthen a lineage-specific null; linked correction retained.", "confounders_present": [ "Targeted fermentation is not all glucose metabolism. Multiple Cre/chemical paradigms strengthen a lineage-specific null; linked correction retained." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 68, "pmid": "15172999", "title": "Akt stimulates aerobic glycolysis in cancer cells.", "citation": "Elstrom RL, Bauer DE, Buzzai M et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer research. 2004.", "doi": "10.1158/0008-5472.CAN-03-2904", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15172999/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15172999/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID15172999", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "Akt-expressing transformed cells", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Akt increased glucose consumption and aerobic glycolysis without increasing oxidative phosphorylation or culture proliferation.", "what_it_does_not_show": "Oncogene activation precedes the switch, and glucose-withdrawal sensitivity does not isolate lactate fermentation from all glucose functions.", "confounders_present": [ "Oncogene activation precedes the switch, and glucose-withdrawal sensitivity does not isolate lactate fermentation from all glucose functions." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } } ], "verification_summary": { "load_bearing_claims_checked": 72, "verified": 72, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC1", "cap": "Β", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Association-only cancer claims cap at Β.", "specific_trigger": "Human and mouse tracing confirms increased glycolytic activity in many tumours, alongside respiration and fuel heterogeneity. This descriptive existence claim is supported without a causal upgrade [33,49–56].", "resulting_ceiling": "Β" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Aerobic glycolysis is a primary causal driver of malignant transformation and sustained tumour growth rather than a metabolic consequence of upstream oncogenic signalling.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "“A perturbation crosses a threshold within the system it was actually run in. A universal cap governs the inference from that system to the hypothesis’s claimed scope.” Cancer rubric02 governs endogenous initiation, maintenance and relapse. Metabolism rubric06 informs flux and redox but does not impose lifespan endpoints on cancer. Positive HK2 and related autochthonous tests receive their scoped causal credit; the broad state-necessity and primacy claims remain Γ because the targeted causal inference is not established, not because the whole convergent literature is re-capped at its weakest member.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID26909577", "gamma_hard_rules_triggered": [], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Human and mouse tracing confirms increased glycolytic activity in many tumours, alongside respiration and fuel heterogeneity. This descriptive existence claim is supported without a causal upgrade [33,49–56].", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID34921016, PMID35547764, PMID31257027, PMID29533781, PMID28425994, PMID25119024, PMID26541605, PMID30819189, PMID20421486, PMID31263025, PMID32580961, PMID29386513, PMID23911236, PMID29854399, PMID31811141, PMID22541435, PMID39303037", "gamma_hard_rules_triggered": [ "General state necessity fails across assessed endogenous tumour contexts despite positive named enzyme dependencies." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Specific HK2 and other metabolic dependencies have positive endogenous causal tests, but the general aerobic fermentation state is not required in all assessed tumours. PKM2 isoform loss is not equivalent to removal of glycolysis; the LDHA SCC null more directly constrains fermentation necessity [44–48,65–67].", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID35547764, PMID25119024, PMID26909577, PMID30819189, PMID31263025, PMID32580961, PMID22541435", "gamma_hard_rules_triggered": [ "The strongest metabolic-first transformation evidence remains cell-based and overexpression-linked; endogenous upstream primacy is unresolved." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Metabolic feedback can activate oncogenic signals in culture, but endogenous KRAS withdrawal, copy-number and effector tests generally place an oncogene before reprogramming. A general glycolysis-first transformation/maintenance model has not crossed its causal threshold [31,35,37–41,57,68].", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "no", "supporting_evidence": [ "[31] Endogenous mutant allele enrichment accompanied progression and a glycolytic/TCA/glutathione metabolic program." ], "what_would_cross_it": "The association/existence statement is not upgraded to a causal proposition by additional tracing alone." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "no", "supporting_evidence": [ "[3] Independent splice-switching ASOs altered PKM isoforms and inhibited xenograft and genetic HCC tumourigenesis.", "[4] mTOR-NEAT1-paraspeckle regulation controlled glycolytic splicing and tumour growth in an oncogene-driven model.", "[13] BACH1-linked glycolysis promoted antioxidant-associated metastasis and BACH1 targeting prevented that increase.", "[15] PKM1 supported tumour growth in defined KRAS/carcinogen models and proliferation in pulmonary neuroendocrine cancers.", "[25] Serine/glycine restriction improved survival in Apc and Myc models, with weaker responses in KRAS-driven cancers.", "[30] Cells surviving KRAS ablation relied more on mitochondrial respiration and supported relapse.", "[32] High-dose vitamin C caused redox-linked GAPDH inhibition and impaired growth in Apc/KRAS mice.", "[35] COX2 deletion attenuated HFD-driven KRAS hyperactivation, glycolysis and dysplasia.", "[38] TFAM loss reduced KRAS-driven tumorigenesis; mitochondrial ROS and glutamine metabolism supported transformation.", "[40] Nix loss delayed PDAC progression and improved survival, while later mitochondrial-clearance compensation allowed progression.", "[41] Pancreatic p38gamma loss reduced glycolytic intermediates/signalling and PDAC, with PFKFB3 pathway epistasis.", "[44] Liver HK2 deletion reduced tumour incidence; WT but not kinase-dead or mitochondrial-binding-deficient HK2 restored cell phenotypes.", "[46] HK2 deletion reduced initiation and maintenance despite HK1 expression, and systemic deletion was therapeutic in mice.", "[48] PKM2 loss delayed onset but tumours eventually grew; lineage reporting assigned residual PKM2 to stroma and showed PKM1-positive proliferation.", "[53] Glo1 ablation increased reactive-metabolite sensitivity and reduced mouse tumour growth.", "[57] KRAS withdrawal established maintenance dependence and controlled glucose routing into anabolic pathways.", "[66] GLS loss alone preserved tumourigenesis with lactate-use compensation; combined LDHA/GLS loss prevented papilloma and carcinoma." ], "what_would_cross_it": "Selectively lower aerobic lactate fermentation while preserving glucose-derived biosynthesis and enzyme scaffolding, with tumour outcomes and orthogonal redox rescue across the prespecified endogenous lineages." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "no", "supporting_evidence": [ "[4] mTOR-NEAT1-paraspeckle regulation controlled glycolytic splicing and tumour growth in an oncogene-driven model.", "[30] Cells surviving KRAS ablation relied more on mitochondrial respiration and supported relapse.", "[31] Endogenous mutant allele enrichment accompanied progression and a glycolytic/TCA/glutathione metabolic program.", "[35] COX2 deletion attenuated HFD-driven KRAS hyperactivation, glycolysis and dysplasia.", "[40] Nix loss delayed PDAC progression and improved survival, while later mitochondrial-clearance compensation allowed progression.", "[41] Pancreatic p38gamma loss reduced glycolytic intermediates/signalling and PDAC, with PFKFB3 pathway epistasis.", "[57] KRAS withdrawal established maintenance dependence and controlled glucose routing into anabolic pathways." ], "what_would_cross_it": "Endogenous physiological flux manipulation must induce or sustain malignant transformation with oncogenic pathways intact, establish temporal precedence, and survive matched epistasis and alternative-function rescue." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "Apc colon tumours retained growth and survival after PKM2 deletion [45]", "Brca1 mammary tumours formed faster after PKM2 deletion [47]", "LDHA-null SCC retained tested tumour outcomes in multiple paradigms [67]", "Increased NADH-shuttle flux reduced fermentation without reducing cell proliferation [64]", "Engineered aspartate bypass increased selected tumour growth but not AsPC-1 growth [28]" ], "note": "Lineage, initiating genotype, stage, nutrient and oxygen boundaries are supported by internal contrasts. These map real dependencies and bypasses but do not establish a universal upstream fermentation state. Normal-cell nucleotide rescue is a specificity comparator, not evidence of cancer primacy." }, "falsification_patterns_met": [ { "pattern": "The nominated metabolic node can be dispensable", "evidence": "LDHA loss preserved SCC outcomes and PKM2 loss had lineage-dependent null, acceleration or delay effects [45,47–48,67].", "downgrade_applied": false }, { "pattern": "Metabolic rate and growth dissociate", "evidence": "Lower fermentation after shuttle modulation did not lower proliferation [64].", "downgrade_applied": false }, { "pattern": "Primary and recurrence states differ", "evidence": "KRAS-surviving cells and endocrine persisters rely more on respiration [26,30].", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Presence mistaken for primacy", "where": "FDG avidity and glycolytic expression are not flux-state necessity [54]." }, { "pitfall": "Enzyme function equated with the nominated metabolic state", "where": "HK2 mitochondrial binding, ENO1 immune regulation and PKM2 noncanonical roles [8,14,44]." }, { "pitfall": "Xenograft capacity equated with endogenous initiation", "where": "PKM isoform replacement and LDHA complementation [11,59]." }, { "pitfall": "Clinical pharmacological failure misread as biological falsification", "where": "IACS exposure was limited by toxicity, preventing a clean efficacy test [60]." }, { "pitfall": "Scope fitted to outcome", "where": "Genotype, tissue, oxygen and baseline treatment state are specified antecedently; responders are not used to define the claim." } ], "causal_tally_audit": { "tally_claimed_by_document": 18, "tally_after_audit": 18, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Only positive endogenous tumour or stage-specific contributions carry the causal flag. Biochemical/cell rescues, tracing, unrescued graft tests and null dispensability contrasts remain informative without being counted as positive broad primacy crossings." ] }, "steelman": { "case_one_rung_higher": "The case for Δ is that glucose uptake can activate oncogenic pathways, metabolic rescue changes tumour phenotypes, and endogenous HK2 deletion strongly alters initiation and maintenance [37,44,46]. Those results establish more than passive metabolism and justify Ε for named dependencies.", "case_one_rung_lower": "The case for Β is that human primacy evidence is mainly observational and fermentation can be dispensable [54,64–67]. It overlooks experimentally demonstrated metabolic-to-signalling feedback and causal contributions in cancer models [10,37,44,46].", "which_rejected": "Reject Δ for general upstream primacy because selective endogenous fermentation-first causation across the registered scope has not been shown. Reject Β as the primary score because mechanistic feedback and scoped causal contributions exist. Retain Γ with clearly displayed real observation and bounded Ε rival models.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: In prespecified autochthonous KRAS, APC and mammary tumour models, independently manipulate cytosolic NADH recycling and lactate fermentation at physiological exposure while preserving glucose uptake, PPP/hexosamine carbon routing and enzyme scaffolding. Apply perturbations before initiation and separately after tumour establishment, with orthogonal flux rescue, matched oncogene signalling and lineage-resolved metastasis/relapse follow-up." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "68 primary reports with 7 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "Primary-subclaim SC3 returns Γ. Cell-level feedback and strong context-specific metabolic contributions make the hypothesis more than association, but no examined evidence set establishes general upstream metabolic primacy across tumour classes. SC2 remains Γ for the registered broad state-necessity claim; named endogenous dependencies reach Ε as a competing model. Weakest-link sensitivity is Β due to descriptive SC1; primary and scope-matched sensitivities are Γ. The real Warburg observation is not labelled refuted." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "The demonstrated nominal contribution is largely execution and amplification downstream of oncogenic signalling, with feedback through redox, YAP/HIF, lactate and immune interactions. HK2 can be required within named models, but necessity of a glucose-phosphorylation enzyme does not establish fermentation as the initiating lesion. Rate limitation and general primacy do not follow from proliferation inhibition.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "The 2024 combined LDHA/GLS deletion study tests the limits of metabolic bypass [66], while the 2024 mitochondrial editing work tests redox and immune consequences [9]. These are discriminating perturbations even where the general primacy claim is not supported.", "justification": "The 2024 combined LDHA/GLS deletion study tests the limits of metabolic bypass [66], while the 2024 mitochondrial editing work tests redox and immune consequences [9]. These are discriminating perturbations even where the general primacy claim is not supported." }, "stability": { "value": "Stable", "trigger": "No verified imminent clinical or endogenous flux-isolation result is used to claim a pending score change. The proposed stage-resolved experiment could move SC3 but is not a known upcoming readout.", "justification": "No verified imminent clinical or endogenous flux-isolation result is used to claim a pending score change. The proposed stage-resolved experiment could move SC3 but is not a known upcoming readout." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Γ", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "Ranking categorical verdict visible; no prior letter used as a target", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": false, "new_level": "Γ", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "In prespecified autochthonous KRAS, APC and mammary tumour models, independently manipulate cytosolic NADH recycling and lactate fermentation at physiological exposure while preserving glucose uptake, PPP/hexosamine carbon routing and enzyme scaffolding. Apply perturbations before initiation and separately after tumour establishment, with orthogonal flux rescue, matched oncogene signalling and lineage-resolved metastasis/relapse follow-up.", "readout": "Incident tumours, clonal growth, maintenance regression and metastatic/relapse burden alongside absolute fermentation, TCA flux, redox, ATP demand and biosynthetic routing", "critical_control": "Catalytic versus scaffold rescue, wild-type and nonmalignant controls, matched oxygen/perfusion and nutrient supply, orthogonal redox instruments, blinded pathology and prespecified tissues/genotypes", "supporting_result": "Physiological fermentation elevation initiates malignant state before oncogenic changes, and selective reversal suppresses the same state despite preserved nonfermentation outputs across the registered lineages", "falsifying_result": "Validated fermentation reduction preserves initiation or maintenance, or effects disappear after biosynthetic/redox rescue while the nominated fermentation state remains altered" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Stage-resolved endogenous flux manipulation that isolates fermentation from glucose-derived biosynthesis and enzyme scaffolding.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Paired lineage-resolved human primary/metastatic tracing, with measured perfusion, substrate exchange and immune/stromal contribution.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Prospectively define metabolic dependence using functional flux rather than FDG or transcript abundance alone.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Test adaptive transporter and nutrient bypass with orthogonal rescue before declaring an enzyme universally necessary.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Read linked corrections and inaccessible full Methods/supplements before promoting precise numerical or translational claims; improve therapeutic windows without treating exposure-limited failures as clean biological nulls.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-05", "reviewer": "Codex", "evidence_base_note": "68 primary reports; cutoff 2026-10-05; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Europe PMC; signed-in Consensus browser discovery and indexed full-text extraction; independent checks against original sections. Zero Consensus API calls.", "skill_version": "5.3", "validator_run": "exact archived v5.3 validator 2.3; see validator.txt", "validator_warnings_addressed": "Phenomenon entry was restated as the preregistered causal claim. No real phenomenon is labelled refuted; warning is explicitly justified.", "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Endogenous genetic natural experiments and therapeutic incidence/survival interventions can reach the upper ladder without an unethical human cancer-induction trial. Named oncogene and metabolic dependencies have strong causal evidence, but the assessed convergence does not establish general fermentation-first primacy. Human tracing gives substrate use rather than intervention-based necessity; phase-I dose limitation and uncontrolled DCA observations do not carry the registered claim further." }, { "kind": "natural_experiment", "available": true, "why_not_sufficient": "Endogenous genetic natural experiments and therapeutic incidence/survival interventions can reach the upper ladder without an unethical human cancer-induction trial. Named oncogene and metabolic dependencies have strong causal evidence, but the assessed convergence does not establish general fermentation-first primacy. Human tracing gives substrate use rather than intervention-based necessity; phase-I dose limitation and uncontrolled DCA observations do not carry the registered claim further." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Endogenous genetic natural experiments and therapeutic incidence/survival interventions can reach the upper ladder without an unethical human cancer-induction trial. Named oncogene and metabolic dependencies have strong causal evidence, but the assessed convergence does not establish general fermentation-first primacy. Human tracing gives substrate use rather than intervention-based necessity; phase-I dose limitation and uncontrolled DCA observations do not carry the registered claim further." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Endogenous genetic natural experiments and therapeutic incidence/survival interventions can reach the upper ladder without an unethical human cancer-induction trial. Named oncogene and metabolic dependencies have strong causal evidence, but the assessed convergence does not establish general fermentation-first primacy. Human tracing gives substrate use rather than intervention-based necessity; phase-I dose limitation and uncontrolled DCA observations do not carry the registered claim further." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": true, "why_not_sufficient": "Endogenous genetic natural experiments and therapeutic incidence/survival interventions can reach the upper ladder without an unethical human cancer-induction trial. Named oncogene and metabolic dependencies have strong causal evidence, but the assessed convergence does not establish general fermentation-first primacy. Human tracing gives substrate use rather than intervention-based necessity; phase-I dose limitation and uncontrolled DCA observations do not carry the registered claim further." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 68, "claims_total": 72, "claims_verified": 72, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 68, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "LDHA reduction and site-specific NBS1 lactylation work link lactate to DNA repair and chemotherapy resistance. Resistance is distinct from initiation; the abstract's anaerobic wording does not redefine aerobic glycolysis as oxygen absence.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C2", "text": "SIX1 transcriptional regulation increased glycolytic genes and tumour growth. A transcriptional driver upstream of metabolism does not establish glycolysis as the primary initiating event.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C3", "text": "Independent splice-switching ASOs altered PKM isoforms and inhibited xenograft and genetic HCC tumourigenesis. Splice replacement is not PKM2 deletion; genotype, increased pyruvate-kinase activity and nonmetabolic functions remain relevant.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C4", "text": "mTOR-NEAT1-paraspeckle regulation controlled glycolytic splicing and tumour growth in an oncogene-driven model. The initiating oncogene and broad RNA-processing changes precede the metabolic phenotype; selective flux mediation is not fully isolated.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C5", "text": "E6/E7 knockdown reduced glycolysis and growth, with IGF2BP2 rescue and MYC-linked regulation. The viral oncogenes sit upstream and rescue affects RNA regulation broadly; this is not proof of glycolysis-first initiation.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C6", "text": "2-DG delayed carcinogenesis and prolonged survival after DEN exposure. 2-DG affects multiple metabolic and glycosylation processes; DEN remains the initiating exposure and no selective metabolic rescue was presented in the abstract.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C7", "text": "Detachment reduced lactate secretion and increased respiratory-inhibitor sensitivity. Culture stress is not an endogenous metastatic lesion; adaptive oxidation challenges a fixed state without establishing universal respiration dependence.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C8", "text": "Distinct ENO1 glycosylation sites regulated catalysis and PD-L1 stability, with tumour and immune effects. One enzyme has separable metabolic and immune functions; site effects cannot all be attributed to glycolytic flux.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C9", "text": "Mt-Nd5 truncation caused redox-linked glycolytic changes and enhanced checkpoint response in models. A glycolytic shift can improve immune treatment response; isogenic cell growth was not substantially changed and human heteroplasmy response is observational.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph3. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C10", "text": "Glycolytic perturbation modulated YAP/TAZ through PFK1-TEAD interaction and altered overgrowth in flies. Feedback can reinforce oncogenic signalling but does not establish endogenous mammalian tumour initiation by flux alone.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C11", "text": "Replacing PKM2 with PKM1 reduced lactate, increased oxygen use and impaired xenograft formation. Transplanted cell replacement does not establish endogenous PKM2 necessity or generalize to every tumour lineage.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C12", "text": "mTORC2 regulated FoxO acetylation and MYC-linked glycolytic reprogramming. Oncogenic signalling is upstream and patient survival correlations are not metabolic initiation evidence.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C13", "text": "BACH1-linked glycolysis promoted antioxidant-associated metastasis and BACH1 targeting prevented that increase. Metastatic amplification after KRAS-driven cancer is distinct from primary transformation and BACH1 has broader transcriptional functions.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C14", "text": "PKM2-PHD3 interactions increased HIF coactivation and glycolytic flux. PKM2 coactivation is a noncanonical enzyme function; loss of a regulator cannot isolate fermentation as the causal driver.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C15", "text": "PKM1 supported tumour growth in defined KRAS/carcinogen models and proliferation in pulmonary neuroendocrine cancers. This counters PKM2-specific universality; active pyruvate kinase can support malignancy in particular lineages.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C16", "text": "SHMT2 lowered pyruvate-kinase activity and oxygen consumption, supporting survival in ischemic glioma regions. Hypoxic survival adaptation differs from aerobic initiation; glycine toxicity and microenvironment shape the dependency.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C17", "text": "Cyclin D1 perturbation reciprocally altered mitochondrial function and metabolic gene expression in mammary models. Cell-cycle control and mitochondrial changes are coupled; the abstract does not isolate metabolic mediation of tumorigenesis.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C18", "text": "Oxidation-resistant PKM2 reduced redox adaptation and impaired xenograft formation under oxidative stress. PPP redox diversion is not equivalent to lactate dependence; transplanted growth retains the cancer-rubric scope cap.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C19", "text": "Src phosphorylation activated HK1/HK2; phosphorylation-site mutation impaired growth and metastatic phenotypes. Src is upstream, and low-glucose HK1 dependence limits claims of universal HK2 dependency.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C20", "text": "IACS-010759 inhibited OXPHOS-dependent tumour growth with energy and aspartate effects. Preclinical therapeutic tolerability did not predict the subsequent human therapeutic window; respiration inhibition is not proof of glycolysis primacy.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C21", "text": "Asparagine restored proliferation and signalling during respiratory impairment; combined restrictions impaired tumour growth. Nutrient availability bypasses a respiratory output in defined contexts; no universal metabolic state is necessary in every tumour.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C22", "text": "Alternative electron acceptors or aspartate restored proliferation after respiratory-chain impairment. Cell proliferation mechanistic rescue is strong within culture but not an endogenous tumour-initiation test.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C23", "text": "PGC-1alpha silencing reduced metastasis without reducing primary tumour growth, separating oxidative motility from proliferation. Stage-specific effects are not universal respiration necessity. Linked erratum details were not fully audited.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C24", "text": "GOT1-dependent aspartate production and supplementation explained proliferation rescue after ETC inhibition. Cell metabolic outputs do not establish the general tumour-driver claim; supraphysiological supplementation and transporter expression matter.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C25", "text": "Serine/glycine restriction improved survival in Apc and Myc models, with weaker responses in KRAS-driven cancers. Dietary amino-acid dependence is genotype-specific and distinct from lactate fermentation; linked erratum is retained.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C26", "text": "Endocrine-tolerant persisters showed OXPHOS reliance; complex-I targeting suppressed tumour regrowth potential. Human neoadjuvant specimens establish markers, not randomized OXPHOS inhibitor efficacy; persistence differs from initiation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C27", "text": "Respiratory leaders and glucose-using followers required different metabolic interventions during collective invasion. Subpopulation culture cooperation does not prove the same dependencies in intact human metastases.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C28", "text": "gpASNase1 increased growth of selected transplanted tumours and bypassed metformin suppression; AsPC-1 growth did not increase. Engineered enzyme sufficiency maps an endogenous nutrient limitation, not universal respiratory necessity or primary cancer initiation.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Methods:paragraph1, 0:Methods:paragraph2, 0:Methods:paragraph11, 0:Methods:paragraph12, 2:Main text (unsectioned body paragraphs):paragraph6, 2:Main text (unsectioned body paragraphs):paragraph7, 2:Main text (unsectioned body paragraphs):paragraph8, 2:Main text (unsectioned body paragraphs):paragraph9, 2:Main text (unsectioned body paragraphs):paragraph10, 2:Main text (unsectioned body paragraphs):paragraph11, 2:Main text (unsectioned body paragraphs):paragraph12. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C29", "text": "High-OXPHOS PDAC subsets responded to phenformin plus gemcitabine in orthotopic models. Clinical response was proposed rather than demonstrated; baseline tumour heterogeneity matters.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C30", "text": "Cells surviving KRAS ablation relied more on mitochondrial respiration and supported relapse. A selected persistence state differs from untreated primary growth. A linked 2026 erratum is retained and its affected details were not audited.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C31", "text": "Endogenous mutant allele enrichment accompanied progression and a glycolytic/TCA/glutathione metabolic program. Genotype precedes rewiring, and early versus advanced tumours differ; enrichment is not proof that metabolism independently initiated cancer.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C32", "text": "High-dose vitamin C caused redox-linked GAPDH inhibition and impaired growth in Apc/KRAS mice. Pleiotropic oxidative toxicity and genotype selection prevent treating this as a clean test of fermentation-only necessity or clinical efficacy.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C33", "text": "Quantitative tracing found suppressed primary-solid-tumour TCA flux and calculated ATP synthesis, with higher TCA flux in metastases. Calculated ATP depends on flux modelling assumptions; increased glycolysis did not imply greater total ATP production or a causal initiating lesion.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C34", "text": "RAS and mutant HDAC4 produced different metabolic adaptations, with transformation without increased lactate in the latter. In vitro engineered transformation does not establish every endogenous tumour route, but refutes a unique cell-model metabolic program.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C35", "text": "COX2 deletion attenuated HFD-driven KRAS hyperactivation, glycolysis and dysplasia. Diet, inflammation and oncogene activation are upstream; COX2 perturbation is not selective glycolytic subtraction.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C36", "text": "Mitochondria-targeted STAT3 mutants supported RAS transformation without canonical nuclear signalling. Engineered protein localization narrows a mitochondrial contribution rather than universal upstream glycolytic causation.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C37", "text": "GLUT3 overexpression increased glucose uptake and activated oncogenic signalling and disorganized architecture; reduced uptake restored polarity. Overexpression and tissue architecture are not endogenous incidence or proof of aerobic lactate flux as sufficient primary cause.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C38", "text": "TFAM loss reduced KRAS-driven tumorigenesis; mitochondrial ROS and glutamine metabolism supported transformation. Mitochondrial output necessity in this model contradicts a simple defective-respiration account without making it universal.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C39", "text": "GTP-dependent KRAS4A binding directly regulated HK1, providing an oncogene-to-metabolic-enzyme link. Direct binding is not itself an endogenous tumour-survival intervention or complete clinical mechanism.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C40", "text": "Nix loss delayed PDAC progression and improved survival, while later mitochondrial-clearance compensation allowed progression. The KRAS-NIX program is upstream of altered flux; delay is not permanent abrogation or generic metabolic sufficiency.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C41", "text": "Pancreatic p38gamma loss reduced glycolytic intermediates/signalling and PDAC, with PFKFB3 pathway epistasis. The kinase has broader signalling roles and sits downstream of KRAS. Linked erratum PMID39957350 limits unaudited details.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C42", "text": "PKM2 activators promoted an active tetramer and reduced xenograft growth. Activity modulation differs from deletion and from PKM1 expression in every lineage; linked correction details were not fully audited.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C43", "text": "PKM1 expression after PKM2 deletion limited nucleotide synthesis; thymine rescued proliferation. This is normal-cell proliferation, a specificity control rather than a cancer-initiating mechanism.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C44", "text": "Liver HK2 deletion reduced tumour incidence; WT but not kinase-dead or mitochondrial-binding-deficient HK2 restored cell phenotypes. Both catalysis and mitochondrial binding were required in the rescue. Reduced glycolysis coexisted with maintained TCA flux; linked correction retained.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph4, 1:Results:paragraph5. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C45", "text": "PKM2 deletion left tumour incidence, multiplicity, survival and nuclear beta-catenin unchanged despite confirmed recombination. PKM2 loss is not removal of all glycolysis; PKM1 compensation and lineage boundaries remain explicit.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph2, 1:Results:paragraph3. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C46", "text": "HK2 deletion reduced initiation and maintenance despite HK1 expression, and systemic deletion was therapeutic in mice. A first glucose-phosphorylation step supports multiple branches and enzyme functions; this does not prove primary fermentation initiation. Linked correction retained.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C47", "text": "PKM2 loss accelerated mammary tumour formation, with heterogeneous PKM1 expression and proliferating PKM2-null cells. An isoform-specific null is a strong boundary, not proof that tumours have no glucose-metabolism requirement.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C48", "text": "PKM2 loss delayed onset but tumours eventually grew; lineage reporting assigned residual PKM2 to stroma and showed PKM1-positive proliferation. Facilitated initiation is distinct from maintenance necessity; bulk expression mixes tumour and stromal compartments.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph11, 2:Results:paragraph12, 2:Results:paragraph14, 1:Methods:paragraph9, 2:Results:paragraph2, 2:Results:paragraph3, 2:Results:paragraph6. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C49", "text": "Human lactate infusion labelled tumour TCA intermediates; MCT1 loss in mouse tumours removed lactate-dependent labelling. Fuel tracing and uptake loss are not proof that lactate oxidation is universally required for growth.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C50", "text": "Tumours showed glycolysis and glucose oxidation with region-dependent use of additional nutrients. Small surgical cohort and tissue heterogeneity limit extrapolation; flux coexistence is not an initiation experiment.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C51", "text": "Circulating lactate supplied TCA carbon in tissues and lung/pancreatic tumours, sometimes exceeding direct glucose contribution. Tracer contribution depends on feeding state and exchange; label incorporation does not alone establish growth necessity.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C52", "text": "Brain tumours oxidized acetate and glucose, with human acetate oxidation linked to ACSS2 expression. Substrate use is observed rather than selectively required; orthotopic models and human samples have distinct access limits.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C53", "text": "Glo1 ablation increased reactive-metabolite sensitivity and reduced mouse tumour growth. Detoxification of a glycolytic byproduct is a consequence vulnerability, not proof of glycolysis-first oncogenesis.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C54", "text": "FDG SUV did not correlate with glycolytic intermediate labelling and instead related to other respiratory substrate markers and proliferation. FDG uptake cannot stand in for measured lactate fermentation or metabolic causal dependence.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C55", "text": "Glucose carbon entered lactate, TCA metabolism, anaplerosis and biosynthetic pools in human brain tumours. Multiple carbon fates contradict a simple fermentation-only picture without measuring causal necessity.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C56", "text": "Three genetically distinct orthotopic GBM lines oxidized glucose and used it for biosynthesis. Patient-derived graft metabolism does not substitute for selective endogenous loss; linked correction retained.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C57", "text": "KRAS withdrawal established maintenance dependence and controlled glucose routing into anabolic pathways. This places a driver oncogene upstream; metabolic branches and KRAS pleiotropy are not isolated by withdrawal alone.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C58", "text": "MCT1 targeting shifted oxidative cells toward glucose use, retarded tumour growth and altered hypoxic-cell survival. Drug selectivity and microenvironmental nutrient competition limit a universal lactate/fermentation interpretation.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C59", "text": "LDHA reduction impaired tumourigenicity and human LDHA complementation reversed the phenotype. Transplantation-linked maintenance is not universal endogenous initiation; oxygen and rescue specificity matter and correction retained.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C60", "text": "IACS-010759 trials could not establish a recommended phase-II dose because target exposure was limited by lactate elevation and neurotoxicity, with limited activity. Dose-limited pharmacology does not refute biological OXPHOS dependence; clinical safety and mechanistic validity are separate.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C61", "text": "DCA altered mitochondrial signals in patient tissue and a small treated cohort, with reversible neuropathy limiting dose. No randomized control or reliable efficacy estimate; biomarker change and clinical indications cannot establish cancer primacy.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C62", "text": "Recurrent cancers showed OXPHOS enrichment and NRF2-related respiratory vulnerability in experimental models. Matched recurrence associations and xenograft inhibition do not show universal dependency or randomized clinical benefit.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C63", "text": "PDH activation reduced NAD+/NADH and proliferation; uncoupling or ATP hydrolysis rescued both despite increased glucose oxidation. A redox/ATP-demand mechanism in cells is not an endogenous cancer-initiation study.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C64", "text": "Increasing NADH-shuttle flux reduced lactate fermentation without reducing proliferation; fermentation correlated with shuttle capacity rather than growth. Short-term cell behaviour and engineered shuttle activity cannot establish long-term tumour-wide dispensability.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 64 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C65", "text": "LDHA inhibition failed to impair melanoma proliferation or tumour growth and activated GCN2-ATF4/glutamine survival programs. An effective adaptive bypass is actual dependency failure under that intervention; synthetic cotargeting does not restore LDHA-only necessity.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 65 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C66", "text": "GLS loss alone preserved tumourigenesis with lactate-use compensation; combined LDHA/GLS loss prevented papilloma and carcinoma. A joint-pathway requirement maps flexibility, not necessity of either individual pathway. Preprint and journal report are one study family.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 66 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph2, 1:RESULTS:paragraph6, 1:RESULTS:paragraph7, 2:DISCUSSION:paragraph0, 2:DISCUSSION:paragraph2, 2:DISCUSSION:paragraph3, 3:MATERIALS AND METHODS:paragraph1. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C67", "text": "LDHA abrogation or induction did not alter tested tumour outcomes despite reduced glycolytic metabolites and FDG uptake. Targeted fermentation is not all glucose metabolism. Multiple Cre/chemical paradigms strengthen a lineage-specific null; linked correction retained.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 67 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph4, 1:Results:paragraph5, 1:Results:paragraph6. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C68", "text": "Akt increased glucose consumption and aerobic glycolysis without increasing oxidative phosphorylation or culture proliferation. Oncogene activation precedes the switch, and glucose-withdrawal sensitivity does not isolate lactate fermentation from all glucose functions.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 68 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "CSC1", "text": "Human and mouse tracing confirms increased glycolytic activity in many tumours, alongside respiration and fuel heterogeneity. This descriptive existence claim is supported without a causal upgrade [33,49–56].", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 7, 9, 17, 27, 31, 33, 34, 49, 50, 51, 52, 54, 55, 56, 62, 68 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-05", "note": "" }, { "id": "CSC2", "text": "Specific HK2 and other metabolic dependencies have positive endogenous causal tests, but the general aerobic fermentation state is not required in all assessed tumours. PKM2 isoform loss is not equivalent to removal of glycolysis; the LDHA SCC null more directly constrains fermentation necessity [44–48,65–67].", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 33, 35, 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 53, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-05", "note": "" }, { "id": "CSC3", "text": "Metabolic feedback can activate oncogenic signals in culture, but endogenous KRAS withdrawal, copy-number and effector tests generally place an oncogene before reprogramming. A general glycolysis-first transformation/maintenance model has not crossed its causal threshold [31,35,37–41,57,68].", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 2, 4, 5, 10, 12, 14, 17, 19, 30, 31, 34, 35, 37, 39, 40, 41, 57, 63, 64, 68 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-05", "note": "" }, { "id": "CH", "text": "Aerobic glycolysis is a real, heterogeneous tumour phenotype and can support specific cancer dependencies. The evidence does not establish it as the general primary event upstream of oncogenic signalling.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 46, 57, 67, 64, 49, 33 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-05", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Chen H, Li Y, Li H et al. NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance. Nature. 2024.", "tier": "A", "kind": "primary", "pmid": "38961290", "doi": "10.1038/s41586-024-07620-9", "url": "https://pubmed.ncbi.nlm.nih.gov/38961290/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID38961290", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. 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Nature. 2017.", "tier": "A", "kind": "primary", "pmid": "28425994", "doi": "10.1038/nature22056", "url": "https://pubmed.ncbi.nlm.nih.gov/28425994/", "status_flags": [ "ErratumIn: PMID28770843" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID28425994", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C25", "CSC2" ] }, { "n": 26, "citation": "Tau S, Chamberlin MD, Yang H et al. Oxidative Phosphorylation Is a Metabolic Vulnerability of Endocrine Therapy-Tolerant Persister Cells in ER+ Breast Cancer. 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The Journal of clinical investigation. 2014.", "tier": "A", "kind": "primary", "pmid": "24316969", "doi": "10.1172/JCI63146", "url": "https://pubmed.ncbi.nlm.nih.gov/24316969/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID24316969", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C37", "CSC3" ] }, { "n": 38, "citation": "Weinberg F, Hamanaka R, Wheaton WW et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proceedings of the National Academy of Sciences of the United States of America. 2010.", "tier": "A", "kind": "primary", "pmid": "20421486", "doi": "10.1073/pnas.1003428107", "url": "https://pubmed.ncbi.nlm.nih.gov/20421486/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID20421486", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C38", "CSC2" ] }, { "n": 39, "citation": "Amendola CR, Mahaffey JP, Parker SJ et al. KRAS4A directly regulates hexokinase 1. 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Cancer discovery. 2019.", "tier": "A", "kind": "primary", "pmid": "31263025", "doi": "10.1158/2159-8290.CD-18-1409", "url": "https://pubmed.ncbi.nlm.nih.gov/31263025/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID31263025", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C40", "CSC2", "CSC3" ] }, { "n": 41, "citation": "Wang F, Qi XM, Wertz R et al. p38γ MAPK Is Essential for Aerobic Glycolysis and Pancreatic Tumorigenesis. 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NMR in biomedicine. 2012.", "tier": "A", "kind": "primary", "pmid": "22419606", "doi": "10.1002/nbm.2794", "url": "https://pubmed.ncbi.nlm.nih.gov/22419606/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID22419606", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C55", "CSC1" ] }, { "n": 56, "citation": "Marin-Valencia I, Yang C, Mashimo T et al. Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo. 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