{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T12:54:46Z","timestamp":1769259286967,"version":"3.49.0"},"reference-count":72,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Gastroenterol."],"abstract":"<jats:p>Metabolic dysfunction-associated steatohepatitis (MASH), along with other chronic liver diseases, leads to progressive fibrosis and, ultimately, cirrhosis. Liver fibrosis is a major cause of global morbidity and mortality. Although past efforts to develop antifibrotic drugs have largely failed, recent advances in MASH metabolic therapies offer new hope. These include both indirect-acting agents such as glucagon-like peptide 1 (GLP-1) analogues, which reduce liver fat by promoting weight loss, and therapies with direct-acting mechanisms on the liver, such as thyroid hormone receptor beta (THR\u03b2) activators and fibroblast growth factor 21 (FGF21) analogues. This perspective summarises emerging antifibrotics, from the fast-evolving class of metabolic therapies through to the more sluggish development of non-metabolic antifibrotics. We consider future therapeutic combinations and patient stratifiers that may impact patient outcomes, and close by asking if fibrosis reversal should be the only goal.<\/jats:p>","DOI":"10.3389\/fgstr.2025.1704078","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T05:16:40Z","timestamp":1769145400000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["MASH and the race for liver antifibrotics"],"prefix":"10.3389","volume":"4","author":[{"given":"Quin","family":"Wills","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2023.03.017","article-title":"Global burden of liver disease: 2023 update","volume":"79","author":"Devarbhavi","year":"2023","journal-title":"J Hepatol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"7083","DOI":"10.1038\/s41598-025-91312-5","article-title":"Global burden of MAFLD, MAFLD-related cirrhosis and MASH-related liver cancer from 1990 to 2021","volume":"15","author":"Guo","year":"2025","journal-title":"Sci Rep"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.1053\/j.gastro.2020.01.043","article-title":"Association between fibrosis stage and outcomes of patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis","volume":"158","author":"Taylor","year":"2020","journal-title":"Gastroenterology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.jhep.2020.02.027","article-title":"Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomised phase III STELLAR trials","volume":"73","author":"Harrison","year":"2020","journal-title":"J Hepatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.11.024","article-title":"A randomised, placebo-controlled trial of emricasan in patients with NASH and F1\u2013F3 fibrosis","volume":"72","author":"Harrison","year":"2020","journal-title":"J Hepatol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31622","article-title":"Combination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis attributable to NASH","volume":"73","author":"Loomba","year":"2021","journal-title":"Hepatology"},{"key":"B7","unstructured":"ClinicalTrials.gov\n          \n          \n          \n          2025"},{"key":"B8","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.cgh.2023.04.003","article-title":"Cenicriviroc lacked efficacy to treat liver fibrosis in nonalcoholic steatohepatitis: AURORA phase III randomised study","volume":"22","author":"Anstee","year":"2024","journal-title":"Clin Gastroenterol Hepatol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1334","DOI":"10.1053\/j.gastro.2019.11.296","article-title":"Effects of belapectin, an inhibitor of galectin-3, in patients with nonalcoholic steatohepatitis with cirrhosis and portal hypertension","volume":"158","author":"Chalasani","year":"2020","journal-title":"Gastroenterology"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2018.07.006","article-title":"Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis","volume":"155","author":"Harrison","year":"2018","journal-title":"Gastroenterology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1056\/NEJMoa2309000","article-title":"A phase 3, randomised, controlled trial of resmetirom in NASH with liver fibrosis","volume":"390","author":"Harrison","year":"2024","journal-title":"N Engl J Med"},{"key":"B12","unstructured":"Noncirrhotic nonalcoholic steatohepatitis with liver fibrosis: developing drugs for treatment: guidance for industry\n          \n          \n          \n          2018"},{"key":"B13","unstructured":"Reflection paper on regulatory requirements for the development of medicinal products for non-alcoholic steatohepatitis (NASH)\n          \n          \n          \n          2023"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2413258","article-title":"Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis","volume":"92","author":"Sanyal","year":"2025","journal-title":"N Engl J Med"},{"key":"B15","unstructured":"FDA approves treatment for serious liver disease known as \u2018MASH\u2019\n          \n          \n          \n          2025"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2502242","article-title":"Efruxifermin in compensated liver cirrhosis caused by MASH","volume":"392","author":"Noureddin","year":"2025","journal-title":"N Engl J Med"},{"key":"B17","unstructured":"Nonalcoholic steatohepatitis with compensated cirrhosis: developing drugs for treatment: guidance for industry\n          \n          \n          \n          2019"},{"key":"B18","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1001\/jamapsychiatry.2024.4789","article-title":"Once-weekly semaglutide in adults with alcohol use disorder: a randomised clinical trial","volume":"82","author":"Hendershot","year":"2025","journal-title":"JAMA Psychiatry"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(24)00246-2","article-title":"Denifanstat for the treatment of metabolic dysfunction-associated steatohepatitis: a multicentre, double-blind, randomised, placebo-controlled, phase 2b trial","volume":"9","author":"Loomba","year":"2024","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2036205","article-title":"A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH","volume":"385","author":"Francque","year":"2021","journal-title":"N Engl J Med"},{"key":"B21","unstructured":"ClinicalTrials.gov\n          \n          \n          \n          2025"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(19)30349-8","article-title":"The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990\u20132017: a systematic analysis for the Global Burden of Disease Study 2017","volume":"5","year":"2020","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"B23","unstructured":"Boehringer Ingelheim begins clinical development of first-in-class treatment for fibrotic diseases\n          \n          \n          \n          2023"},{"key":"B24","unstructured":"Alentis announces positive topline results from two studies of lixudebart (ALE.F02) in patients with ANCA-RPGN and advanced liver fibrosis\n          \n          \n          \n          2025"},{"key":"B25","unstructured":"Boehringer Ingelheim seals new oncology antibody partnership and reports progress in several pipeline projects\n          \n          \n          \n          2025"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03406-8","article-title":"Autologous macrophage therapy for liver cirrhosis: a phase 2 open-label randomised controlled trial","volume":"31","author":"Brennan","year":"2025","journal-title":"Nat Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1188049","article-title":"From bench to bedside: the history and progress of CAR T cell therapy","volume":"14","author":"Mitra","year":"2023","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2025.03.008","article-title":"Can we talk? The cryptic communications of hepatic stellate cells in lipid metabolism","volume":"37","author":"Friedman","year":"2025","journal-title":"Cell Metab"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3390\/ph18040507","article-title":"Targeting hepatic stellate cells for the prevention and treatment of liver cirrhosis and hepatocellular carcinoma: strategies and clinical translation","volume":"18","author":"Xiong","year":"2025","journal-title":"Pharmaceuticals"},{"key":"B30","doi-asserted-by":"publisher","first-page":"2025.02.25.640143","DOI":"10.1101\/2025.02.25.640143","article-title":"In vivo anti-FAP CAR T therapy reduces fibrosis and restores liver homeostasis in metabolic dysfunction-associated steatohepatitis","author":"Yashaswini","year":"2025","journal-title":"bioRxiv"},{"key":"B31","unstructured":"Pliant Therapeutics announces successful completion of PLN-1474 phase 1 study and development transition to global pharmaceutical partner\n          \n          \n          \n          2021"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13581","article-title":"Pharmacokinetics, safety, and tolerability of BMS-986263, a lipid nanoparticle containing HSP47 siRNA, in participants with hepatic impairment","volume":"16","author":"Qosa","year":"2023","journal-title":"Clin Transl Sci"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32181","article-title":"BMS-986263 in patients with advanced hepatic fibrosis: 36-week results from a randomised, placebo-controlled phase 2 trial","volume":"75","author":"Lawitz","year":"2022","journal-title":"Hepatology"},{"key":"B34","unstructured":"ClinicalTrials.gov\n          \n          \n          \n          2024"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/s40261-024-01395-7","article-title":"Single-dose pharmacokinetics and safety of the oral galectin-3 inhibitor, selvigaltin (GB1211), in participants with hepatic impairment","volume":"44","author":"Aslanis","year":"2024","journal-title":"Clin Drug Investig"},{"key":"B36","unstructured":"ClinicalTrials.gov\n          \n          \n          \n          2021"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30946","article-title":"The 20% rule of NASH progression: the natural history of advanced fibrosis and cirrhosis caused by NASH","volume":"70","author":"Loomba","year":"2019","journal-title":"Hepatology"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03283-1","article-title":"Data-driven cluster analysis identifies distinct types of metabolic dysfunction-associated steatotic liver disease","volume":"30","author":"Raverdy","year":"2024","journal-title":"Nat Med"},{"key":"B39","doi-asserted-by":"publisher","first-page":"892","DOI":"10.1002\/hep.31108","article-title":"Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study","volume":"72","author":"Ratziu","year":"2020","journal-title":"Hepatology"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16061214","article-title":"Metabolic dysfunction-associated steatohepatitis and progression to hepatocellular carcinoma: a literature review","volume":"16","author":"Ghazanfar","year":"2024","journal-title":"Cancers"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqaa134","article-title":"NAFLD and NASH in postmenopausal women: implications for diagnosis and treatment","volume":"161","author":"DiStefano","year":"2020","journal-title":"Endocrinology"},{"key":"B42","doi-asserted-by":"publisher","first-page":"9","DOI":"10.20517\/mtod.2023.45","article-title":"Racial and ethnic disparities in metabolic dysfunction-associated steatotic liver disease","volume":"4","author":"Gulati","year":"2024","journal-title":"Metab Target Organ Damage"},{"key":"B43","doi-asserted-by":"publisher","first-page":"17608","DOI":"10.1038\/s41598-022-22729-5","article-title":"The additive effect of genetic and metabolic factors in the pathogenesis of nonalcoholic fatty liver disease","volume":"12","author":"Seko","year":"2022","journal-title":"Sci Rep"},{"key":"B44","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.jhep.2024.12.046","article-title":"AZD2693, a PNPLA3 antisense oligonucleotide, for the treatment of MASH in 148M homozygous participants: two randomised phase I trials","volume":"83","author":"Armisen","year":"2025","journal-title":"J Hepatol"},{"key":"B45","unstructured":"ClinicalTrials.gov\n          \n          \n          \n          2025"},{"key":"B46","unstructured":"ClinicalTrials.gov\n          \n          \n          \n          2025"},{"key":"B47","unstructured":"Arrowhead Pharmaceuticals gains full rights to NASH candidate ARO-PNPLA3 with promising phase 1 results\n          \n          \n          \n          2023"},{"key":"B48","doi-asserted-by":"publisher","first-page":"e2217543120","DOI":"10.1073\/pnas.2217543120","article-title":"Inhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis","volume":"120","author":"Luukkonen","year":"2023","journal-title":"Proc Natl Acad Sci USA"},{"key":"B49","unstructured":"ClinicalTrials.gov\n          \n          \n          \n          2025"},{"key":"B50","unstructured":"ClinicalTrials.gov\n          \n          \n          \n          2025"},{"key":"B51","unstructured":"Inipharm to present phase 1 pharmacokinetic data for INI-822\n          \n          \n          \n          2024"},{"key":"B52","first-page":"6","article-title":"Phase 3 ESSENCE trial: semaglutide in metabolic dysfunction-associated steatohepatitis","volume":"20","year":"2024","journal-title":"Gastroenterol Hepatol (N Y)"},{"key":"B53","unstructured":"Serious liver injury being observed in patients without cirrhosis taking Ocaliva (obeticholic acid) to treat primary biliary cholangitis\n          \n          \n          \n          2024"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2022.12.025","article-title":"Rational combination therapy for NASH: insights from clinical trials and error","volume":"78","author":"Ratziu","year":"2023","journal-title":"J Hepatol"},{"key":"B55","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1056\/NEJMoa2401943","article-title":"Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis","volume":"391","author":"Loomba","year":"2024","journal-title":"N Engl J Med"},{"key":"B56","unstructured":"Novo Nordisk successfully completes phase 1b\/2a trial with subcutaneous amycretin in people with overweight or obesity\n          \n          \n          \n          2025"},{"key":"B57","unstructured":"Boehringer receives US FDA Breakthrough Therapy designation and initiates two phase III trials in MASH for survodutide\n          \n          \n          \n          2024"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2301972","article-title":"Triple-hormone-receptor agonist retatrutide for obesity\u2014a phase 2 trial","volume":"389","author":"Jastreboff","year":"2023","journal-title":"N Engl J Med"},{"key":"B59","unstructured":"Lilly\u2019s triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful Phase 3 trial"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2015.04.014","article-title":"Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients","volume":"149","author":"Lassailly","year":"2015","journal-title":"Gastroenterology"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1097\/MOG.0000000000000524","article-title":"Fibrosis reversal after hepatitis C virus elimination","volume":"35","author":"Rockey","year":"2019","journal-title":"Curr Opin Gastroenterol"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(23)00272-8","article-title":"Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial","volume":"8","author":"Harrison","year":"2023","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"B63","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1056\/NEJMoa2304286","article-title":"Randomised, controlled trial of the FGF21 analogue pegozafermin in NASH","volume":"389","author":"Loomba","year":"2023","journal-title":"N Engl J Med"},{"key":"B64","article-title":"Once-monthly efimosfermin alfa (BOS-580) in metabolic dysfunction-associated steatohepatitis with F2\/F3 fibrosis: results from a 24-week, randomized, double-blind, placebo-controlled, phase 2 trial","volume":"20","year":"2024","journal-title":"Gastroenterol Hepatol (N Y)"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2025.02.041","article-title":"Prognostic implications of recompensation of decompensated cirrhosis after SVR in patients with hepatitis C","volume":"83","author":"S\u00e1nchez-Torrijos","year":"2025","journal-title":"J Hepatol"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.10.016","article-title":"HCC surveillance after SVR in patients with F3\/F4 fibrosis","volume":"74","author":"Ioannou","year":"2021","journal-title":"J Hepatol"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(25)00315-0","article-title":"LBO-006 Belapectin at 2 mg\/kg\/LBW reduces varices development in MASH cirrhosis with portal hypertension: results from the NAVIGATE trial","volume":"82","author":"Alkhouri","year":"2025","journal-title":"J Hepatol"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.3390\/cells11142221","article-title":"Role of hepatocyte senescence in the activation of hepatic stellate cells and liver fibrosis progression","volume":"11","author":"Wijayasiri","year":"2022","journal-title":"Cells"},{"key":"B69","doi-asserted-by":"publisher","first-page":"1666","DOI":"10.1016\/j.cell.2024.02.023","article-title":"First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure","volume":"187","author":"Zwirner","year":"2024","journal-title":"Cell"},{"key":"B70","unstructured":"LyGenesis announces first patient dosed in its phase 2a clinical trial of a first-in-class regenerative cell therapy for patients with end-stage liver disease\n          \n          \n          \n          2024"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1111\/febs.13665","article-title":"TGF-\u03b2 signalling and liver disease","volume":"283","author":"Fabregat","year":"2016","journal-title":"FEBS J"},{"key":"B72","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1038\/s41536-023-00337-9","article-title":"MFAP4: a promising target for enhanced liver regeneration and chronic liver disease treatment","volume":"8","author":"Iakovleva","year":"2023","journal-title":"NPJ Regener Med"}],"container-title":["Frontiers in Gastroenterology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgstr.2025.1704078\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T05:16:43Z","timestamp":1769145403000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgstr.2025.1704078\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,23]]},"references-count":72,"alternative-id":["10.3389\/fgstr.2025.1704078"],"URL":"https:\/\/doi.org\/10.3389\/fgstr.2025.1704078","relation":{},"ISSN":["2813-1169"],"issn-type":[{"value":"2813-1169","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,23]]},"article-number":"1704078"}}