{
  "cutoff": "2026-10-13",
  "note": "Selected publication milestones, not an exhaustive history or discovery priority claim.",
  "milestones": [
    {
      "pmid": "19827166",
      "year": "2010",
      "title": "Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.",
      "doi": "10.1002/hep.23276",
      "url": "https://pubmed.ncbi.nlm.nih.gov/19827166/",
      "interpretation": "Randomized assigned lifestyle improves NAS and steatosis; current component definitions and achieved-loss strata remain distinct."
    },
    {
      "pmid": "21794038",
      "year": "2011",
      "title": "Weight loss amelioration of non-alcoholic steatohepatitis linked to shifts in hepatic ceramide expression and serum ceramide levels.",
      "doi": "10.1111/j.1872-034X.2011.00815.x",
      "url": "https://pubmed.ncbi.nlm.nih.gov/21794038/",
      "interpretation": "A shared lifestyle-trial molecular follow-up adds ceramide leads rather than an independent clinical outcome unit."
    },
    {
      "pmid": "23485520",
      "year": "2013",
      "title": "The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease.",
      "doi": "10.1016/j.jhep.2013.02.012",
      "url": "https://pubmed.ncbi.nlm.nih.gov/23485520/",
      "interpretation": "Mediterranean-diet fat improvement without different loss separates diet composition from weight mediation."
    },
    {
      "pmid": "25865049",
      "year": "2015",
      "title": "Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis.",
      "doi": "10.1053/j.gastro.2015.04.005",
      "url": "https://pubmed.ncbi.nlm.nih.gov/25865049/",
      "interpretation": "Large paired-biopsy lifestyle cohort makes achieved-loss resolution and regression associations visible."
    },
    {
      "pmid": "26608256",
      "year": "2016",
      "title": "Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.",
      "doi": "10.1016/S0140-6736(15)00803-X",
      "url": "https://pubmed.ncbi.nlm.nih.gov/26608256/",
      "interpretation": "LEAN supplies a distinct randomized drug histology positive with incomplete endpoint biopsies."
    },
    {
      "pmid": "27322798",
      "year": "2016",
      "title": "Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial.",
      "doi": "10.7326/M15-1774",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27322798/",
      "interpretation": "Pioglitazone improves pathology despite weight gain, challenging universal weight-loss necessity."
    },
    {
      "pmid": "27521509",
      "year": "2017",
      "title": "Exercise Reduces Liver Lipids and Visceral Adiposity in Patients With Nonalcoholic Steatohepatitis in a Randomized Controlled Trial.",
      "doi": "10.1016/j.cgh.2016.07.031",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27521509/",
      "interpretation": "Weight-maintained exercise reduces hepatic fat without proving inflammation or fibrosis reversal."
    },
    {
      "pmid": "29333665",
      "year": "2018",
      "title": "Clinical and metabolic effects associated with weight changes and obeticholic acid in non-alcoholic steatohepatitis.",
      "doi": "10.1111/apt.14492",
      "url": "https://pubmed.ncbi.nlm.nih.gov/29333665/",
      "interpretation": "FLINT achieved-weight posthoc analysis illustrates additive response and nonrandom mediation limits."
    },
    {
      "pmid": "31813633",
      "year": "2019",
      "title": "Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.",
      "doi": "10.1016/S0140-6736(19)33041-7",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31813633/",
      "interpretation": "Obeticholic acid separates a fibrosis positive from a nonsignificant steatohepatitis-resolution outcome."
    },
    {
      "pmid": "32553765",
      "year": "2020",
      "title": "Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis.",
      "doi": "10.1053/j.gastro.2020.06.006",
      "url": "https://pubmed.ncbi.nlm.nih.gov/32553765/",
      "interpretation": "Five-year bariatric biopsies reveal durable observed resolution/regression with selective follow-up."
    },
    {
      "pmid": "33185364",
      "year": "2021",
      "title": "A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis.",
      "doi": "10.1056/NEJMoa2028395",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33185364/",
      "interpretation": "Daily semaglutide shows resolution efficacy while categorical fibrosis is nonsignificant."
    },
    {
      "pmid": "34670042",
      "year": "2021",
      "title": "A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH.",
      "doi": "10.1056/NEJMoa2036205",
      "url": "https://pubmed.ncbi.nlm.nih.gov/34670042/",
      "interpretation": "Lanifibranor demonstrates clinical-pathology efficacy despite weight gain and dose-specific significance."
    },
    {
      "pmid": "34762106",
      "year": "2021",
      "title": "Association of Bariatric Surgery With Major Adverse Liver and Cardiovascular Outcomes in Patients With Biopsy-Proven Nonalcoholic Steatohepatitis.",
      "doi": "10.1001/jama.2021.19569",
      "url": "https://pubmed.ncbi.nlm.nih.gov/34762106/",
      "interpretation": "SPLENDOR contributes observational long-term surgery-event evidence rather than a surrogate-based lifestyle proof."
    },
    {
      "pmid": "36508737",
      "year": "2023",
      "title": "Effect of Calorie-Unrestricted Low-Carbohydrate, High-Fat Diet Versus High-Carbohydrate, Low-Fat Diet on Type 2 Diabetes and Nonalcoholic Fatty Liver Disease : A Randomized Controlled Trial.",
      "doi": "10.7326/M22-1787",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36508737/",
      "interpretation": "Randomized diet metabolic/weight improvements do not guarantee a biopsy difference."
    },
    {
      "pmid": "36934740",
      "year": "2023",
      "title": "Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial.",
      "doi": "10.1016/S2468-1253(23)00068-7",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36934740/",
      "interpretation": "Compensated cirrhosis semaglutide has weight/MRI-fat benefit without a positive histologic endpoint."
    },
    {
      "pmid": "37088093",
      "year": "2023",
      "title": "Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trial.",
      "doi": "10.1016/S0140-6736(23)00634-7",
      "url": "https://pubmed.ncbi.nlm.nih.gov/37088093/",
      "interpretation": "BRAVES provides an actual surgery-versus-lifestyle/best-care randomized biopsy comparison."
    },
    {
      "pmid": "38324483",
      "year": "2024",
      "title": "A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.",
      "doi": "10.1056/NEJMoa2309000",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38324483/",
      "interpretation": "MAESTRO-NASH establishes resmetirom histology efficacy for a separate liver-directed exposure."
    },
    {
      "pmid": "38856224",
      "year": "2024",
      "title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.",
      "doi": "10.1056/NEJMoa2401943",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38856224/",
      "interpretation": "SYNERGY-NASH adds tirzepatide pathology positives, with missing biopsies and an attached erratum."
    },
    {
      "pmid": "38914313",
      "year": "2024",
      "title": "Histological improvements following energy restriction and exercise: The role of insulin resistance in resolution of MASH.",
      "doi": "10.1016/j.jhep.2024.06.017",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38914313/",
      "interpretation": "A newer small lifestyle RCT reports explicit component/resolution benefits with average fibrosis unchanged and an unresolved count discrepancy."
    },
    {
      "pmid": "40305708",
      "year": "2025",
      "title": "Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis.",
      "doi": "10.1056/NEJMoa2413258",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40305708/",
      "interpretation": "ESSENCE interim 72-week semaglutide pathology positives precede its ongoing longer clinical phase."
    },
    {
      "pmid": "41066427",
      "year": "2025",
      "title": "Relationship Between Metabolic and Histological Responses in People With Metabolic Dysfunction- Associated Steatohepatitis With and Without Type 2 Diabetes: Participant-Level Exploratory Analysis of the SYNERGY-NASH Trial With Tirzepatide.",
      "doi": "10.2337/dc25-1306",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41066427/",
      "interpretation": "SYNERGY responder/mediation analysis generates weight-related leads without randomized mediator identity."
    },
    {
      "pmid": "42765724",
      "year": "2026",
      "title": "GLP-1-based treatments and long-term clinical outcomes in MASLD amongst older adults: a retrospective cohort study.",
      "doi": "10.1093/ageing/afag281",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42765724/",
      "interpretation": "Older-adult GLP1 cohort associates exposure with hepatic outcomes while MACE is null; observational event evidence remains separate."
    }
  ],
  "gaps": [
    "Independent adequately powered current-resolution replication of assigned lifestyle in baseline MASH.",
    "Source clarification of the nine-resolution/eight-ballooning-zero inconsistency in PMID38914313.",
    "Isolated weight versus activity, diet composition and peripheral metabolic mediation.",
    "Prospective stage/diabetes interaction mapping and paired-biopsy missingness sensitivity.",
    "Controlled lifestyle fibrosis improvement and durability beyond active histology response.",
    "Hard hepatic events and harms beyond short selected cohorts; full supplements and all complete papers remain unaudited."
  ],
  "decisive_experiment": "A multicentre lifestyle-versus-matched-support randomized trial enrolls baseline-biopsy MASH adults, stratifies fibrosis stage and diabetes before outcomes, and measures independently read paired inflammation/ballooning resolution at 52–104 weeks. Factorial diet/exercise and prospectively controlled energy/weight trajectories distinguish package efficacy from isolated mediator claims; retain all assigned participants and specify missing-biopsy sensitivity analyses. Extend blinded hepatic event follow-up."
}