{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:43:14Z","timestamp":1790624594589,"version":"4.1.0"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"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. Pharmacol."],"abstract":"<jats:p>Metabolic dysfunction-associated steatotic liver disease (MASLD), affecting nearly one-third of adults worldwide, encompasses a spectrum from steatosis to steatohepatitis (MASH), advanced fibrosis, cirrhosis, and hepatocellular carcinoma, with fibrosis stage as the primary determinant of liver-related outcomes and cardiovascular disease as the leading cause of mortality. Despite robust evidence that lifestyle interventions achieving \u226510% weight loss induce fibrosis regression in many patients, sustained success in routine practice remains elusive\u2014realised in fewer than 15% of individuals\u2014exposing a critical efficacy-effectiveness gap that demands pharmacologic therapy for those with clinically significant fibrosis. The period 2024\u20132026 has marked a transformative shift, with resmetirom (thyroid hormone receptor-\u03b2 agonist) gaining accelerated approval in 2024 as the first agent to meet histologic endpoints in MASH, followed by semaglutide (GLP-1 receptor agonist) in 2025, both demonstrating substantial MASH resolution and fibrosis improvement in phase 3 trials; a diverse pipeline, including tirzepatide, efruxifermin, lanifibranor, denifanstat, and dual-incretin agonists, has yielded promising histologic and metabolic outcomes, with several advancing to phase 3 and updated guidelines endorsing pharmacotherapy for F2\u2013F3 MASH, prioritising comorbidity-guided selection and synergy with lifestyle modification. Yet, these histologic gains must now be translated into reduced morbidity and mortality through an ambitious agenda of long-term outcome trials, precision biomarkers, and equitable, multidisciplinary care models.<\/jats:p>","DOI":"10.3389\/fphar.2026.1815576","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T06:52:45Z","timestamp":1788159165000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["A new era in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD): clinical breakthroughs and challenges"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhifu","family":"You","sequence":"first","affiliation":[{"name":"Department I of Gastroenterology, First Affiliated Hospital of Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linglong","family":"Yang","sequence":"additional","affiliation":[{"name":"Department I of Gastroenterology, First Affiliated Hospital of Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanhao","family":"Long","sequence":"additional","affiliation":[{"name":"Department I of Gastroenterology, First Affiliated Hospital of Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongye","family":"You","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, South Hospital of Qiqihar Traditional Chinese Medicine Hospital","place":["Qiqihar, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, South Hospital of Qiqihar Traditional Chinese Medicine Hospital","place":["Qiqihar, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.1097\/HEP.0000000000001608","article-title":"Semaglutide therapy for metabolic dysfunction-associated steatohepatitis: november 2025 updates to AASLD practice guidance","volume":"83","author":"Bansal","year":"2026","journal-title":"Hepatology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1016\/j.jhep.2024.12.045","article-title":"Pan-PPAR agonist lanifibranor improves insulin resistance and hepatic steatosis in patients with T2D and MASLD","volume":"82","author":"Barb","year":"2025","journal-title":"J. Hepatol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.cct.2017.07.015","article-title":"Design and rationale for a real-world observational cohort of patients with nonalcoholic fatty liver disease: the TARGET-NASH study","volume":"61","author":"Barritt","year":"2017","journal-title":"Contemp. Clin. Trials"},{"key":"B4","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1097\/MCG.0000000000002232","article-title":"Association of NAFLD and cardiovascular events: a systematic review and meta-analysis","volume":"60","author":"Bhatia","year":"2026","journal-title":"J. Clin. Gastroenterol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2499","DOI":"10.1016\/j.cgh.2024.12.039","article-title":"Biomarkers of histological response in lanifibranor-treated patients with metabolic dysfunction-associated steatohepatitis","volume":"23","author":"Boursier","year":"2025","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2074","DOI":"10.2337\/dc25-1306","article-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","volume":"48","author":"Caussy","year":"2025","journal-title":"Diabetes Care"},{"key":"B7","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1016\/j.tem.2024.02.001","article-title":"Current status and future perspectives of FGF21 analogues in clinical trials","volume":"35","author":"Chui","year":"2024","journal-title":"Trends Endocrinol. Metab."},{"key":"B8","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1016\/j.jhep.2024.04.031","article-title":"EAftSoD, (EASO). EAftSoO: EASeasl-easd-easoinical practice guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD)","volume":"81","year":"2024","journal-title":"J. Hepatol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1055\/a-2253-9181","article-title":"Tailored model of care for patients with metabolic dysfunction-associated steatotic liver disease","volume":"44","author":"El-Kassas","year":"2024","journal-title":"Semin. Liver Dis."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2919","DOI":"10.1038\/s41591-023-02603-1","article-title":"Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial","volume":"29","author":"Harrison","year":"2023","journal-title":"Nat. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1056\/NEJMoa2309000","article-title":"A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis","volume":"390","author":"Harrison","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.jhep.2024.07.006","article-title":"Effect of pemvidutide, a GLP-1\/glucagon dual receptor agonist, on MASLD: a randomized, double-blind, placebo-controlled study","volume":"82","author":"Harrison","year":"","journal-title":"J. Hepatol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.cgh.2024.02.022","article-title":"Safety and efficacy of efruxifermin in combination with a GLP-1 receptor agonist in patients with NASH\/MASH and type 2 diabetes in a randomized phase 2 study","volume":"23","author":"Harrison","year":"","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"846","DOI":"10.2337\/dc25-0241","article-title":"Cardiovascular and kidney outcomes and mortality with long-acting injectable and oral glucagon-like peptide 1 receptor agonists in individuals with type 2 diabetes: a systematic review and meta-analysis of randomized trials","volume":"48","author":"Lee","year":"2025","journal-title":"Diabetes Care"},{"key":"B15","doi-asserted-by":"publisher","first-page":"180","DOI":"10.3390\/diseases12080180","article-title":"Practice recommendations for the management of MASLD in primary care: consensus results","volume":"12","author":"Lionis","year":"2024","journal-title":"Diseases"},{"key":"B16","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":"","journal-title":"N. Engl. J. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1090","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":"","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1016\/S0140-6736(25)00979-1","article-title":"Antisense oligonucleotide DGAT-2 inhibitor, ION224, for metabolic dysfunction-associated steatohepatitis (ION224-CS2): results of a 51-week, multicentre, randomised, double-blind, placebo-controlled, phase 2 trial","volume":"406","author":"Loomba","year":"2025","journal-title":"Lancet"},{"key":"B19","doi-asserted-by":"publisher","first-page":"154170","DOI":"10.1016\/j.metabol.2020.154170","article-title":"Complications, morbidity and mortality of nonalcoholic fatty liver disease","author":"Mantovani","year":"2020","journal-title":"Metabolism"},{"key":"B20","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1016\/S0140-6736(25)01073-6","article-title":"Safety and efficacy of once-weekly efruxifermin versus placebo in metabolic dysfunction-associated steatohepatitis (HARMONY): 96-week results from a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial","volume":"406","author":"Noureddin","year":"","journal-title":"Lancet"},{"key":"B21","doi-asserted-by":"publisher","first-page":"2413","DOI":"10.1056\/NEJMoa2502242","article-title":"Efruxifermin in compensated liver cirrhosis caused by MASH","volume":"392","author":"Noureddin","year":"","journal-title":"N. Engl. J. Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2644","DOI":"10.1016\/S0140-6736(25)02114-2","article-title":"Safety and efficacy of weekly pemvidutide versus placebo for metabolic dysfunction-associated steatohepatitis (IMPACT): 24-week results from a multicentre, randomised, double-blind, phase 2b study","volume":"406","author":"Noureddin","year":"","journal-title":"Lancet"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1111\/apt.70382","article-title":"Effects of resmetirom on metabolic-dysfunction associated steatohepatitis in patients with weight loss and\/or diabetes taking glucagon-like Peptide-1 receptor agonists and other diabetes therapies: a secondary analysis of the MAESTRO-NASH trial","volume":"62","author":"Noureddin","year":"","journal-title":"Aliment. Pharmacol. Ther."},{"key":"B24","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1016\/s2468-1253(22)00165-0","article-title":"The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis","volume":"7","author":"Riazi","year":"2022","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1056\/NEJMoa2401755","article-title":"A phase 2 randomized trial of survodutide in MASH and fibrosis","volume":"391","author":"Sanyal","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2089","DOI":"10.1056\/NEJMoa2413258","article-title":"Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis","volume":"392","author":"Sanyal","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1136\/gutjnl-2023-330595","article-title":"MASLD: a systemic metabolic disorder with cardiovascular and malignant complications","volume":"73","author":"Targher","year":"2024","journal-title":"Gut"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1097\/hep.0000000000000004","article-title":"The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review","volume":"77","author":"Younossi","year":"2023","journal-title":"Hepatology"},{"key":"B29","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1136\/gutjnl-2025-337431","article-title":"Combination therapies for metabolic dysfunction-associated steatohepatitis: challenges and opportunities","volume":"75","author":"Zhou","year":"2025","journal-title":"Gut"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1815576\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T06:52:46Z","timestamp":1788159166000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1815576\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,31]]},"references-count":29,"alternative-id":["10.3389\/fphar.2026.1815576"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1815576","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,31]]},"article-number":"1815576"}}