Current therapeutic landscape and future treatment perspectives of MASH.

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH), the progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD), is a heterogeneous and systemic disease that confers risk not only for cirrhosis and hepatocellular carcinoma (HCC) but also for extrahepatic complications including cardiovascular disease and chronic kidney disease. Over the past decade, numerous late-stage clinical trials have advanced the therapeutic landscape of MASH, culminating in a pivotal inflection point with accelerated approval of the thyroid hormone receptor-β (THRβ) agonist resmetirom and the glucagon-like peptide-1 receptor (GLP-1R) agonist semaglutide, establishing pharmacological options for patients with non-cirrhotic MASH and fibrosis. Concurrently, growing evidence indicates that MASH comprises distinct, partially overlapping disease subsets, ranging from liver-centric phenotypes with accelerated fibrogenesis and liver-related outcomes to cardiometabolic phenotypes characterized by insulin resistance and increased cardiovascular risk. This suggests that optimal treatment efficacy will require stratified and potentially combinatorial approaches. In addition to lifestyle interventions, a cornerstone of MASLD management, pharmacotherapies targeting metabolic dysfunction (including PPAR agonists, FGF21 analogues or incretin-based and glucagon-based therapies), fibrogenesis, inflammation and/or the gut-liver axis are emerging. In this Review, we summarize the therapeutic landscape for MASH and discuss how recent advances in disease phenotyping and biomarkers may enable a transition towards personalized therapy.