Pharmacotherapy for MASLD/MASH: approved therapies, drug repurposing, and emerging mechanism-based candidates.

Abstract

INTRODUCTION Metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASLD/MASH) pharmacotherapy is changing rapidly after the approval of resmetirom and semaglutide for selected adults with noncirrhotic MASH and F2-F3 fibrosis; management must also address obesity, type 2 diabetes, dyslipidemia, cardiovascular risk, and kidney disease. AREAS COVERED This structured narrative review evaluates approved, comorbidity-directed, repurposed, and emerging therapies according to mechanism, regulatory status, endpoint strength, safety, interactions, and implementation. PubMed and ClinicalTrials.gov were searched without a lower date limit through September 2026 and supplemented by U.S. and European regulatory documents, society guidance, randomized trials, systematic reviews, meta-analyses, and selected mechanistic studies. Therapies include thyroid hormone receptor-beta agonism, incretin and glucagon-containing agonists, peroxisome proliferator-activated receptor pathways, sodium-glucose cotransporter 2 inhibition, de novo lipogenesis/fatty acid synthase inhibition, fibroblast growth factor 21 analogues, lipid/remnant pharmacology, farnesoid X receptor signaling, antioxidants, and lower-evidence repurposing candidates. EXPERT OPINION Resmetirom and semaglutide anchor approved MASH-directed treatment in eligible F2-F3 disease, while comorbidity-directed therapy should be individualized by liver stage and cardiometabolic priorities. Tirzepatide, FGF21 analogues, denifanstat, and rational combinations may broaden treatment, but cross-trial comparisons and surrogate endpoints require cautious interpretation.