Study summary · research use only
Therapeutic horizons in metabolic dysfunction-associated steatohepatitis
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This review discusses metabolic dysfunction-associated steatohepatitis (MASH), a progressive inflammatory form of MASLD linked to obesity and type 2 diabetes, in human clinical literature. It covers pharmacological treatments in advanced development, including incretin-based therapies (GLP-1, dual, and triple agonists), metabolic modulators (PPAR, FGF21, THR-β agonists), and fatty acid synthase inhibitors, and notes current regulatory approval relies on histological endpoints, with growing interest in noninvasive biomarkers. The review describes trials of semaglutide, tirzepatide, survodutide, lanifibranor, pegozafermin, and resmetirom as showing results in resolving MASH and improving fibrosis, alongside unresolved questions about treatment duration, response variation, and long-term adherence. It also discusses genetic variants such as PNPLA3 polymorphisms, emerging molecular biomarkers, and the potential role of artificial intelligence in trial design and drug development.
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH), the progressive inflammatory form of MASLD, is now a leading cause of chronic liver disease worldwide. Driven by obesity and type 2 diabetes, MASH significantly increases the risk of cirrhosis, hepatocellular carcinoma, and liver failure. While public health interventions remain essential, therapeutic strategies targeting metabolic dysfunction, inflammation, and fibrosis are urgently needed. This Review focuses on pharmacological treatments in advanced development, including incretin-based therapies (GLP-1, dual, and triple agonists), metabolic modulators (PPAR, FGF21, and THR-β agonists), and novel agents such as fatty acid synthase inhibitors. Current regulatory approval is based on histological end points, with increasing interest in noninvasive biomarkers and personalized treatment approaches. Recent trials with agents such as semaglutide, tirzepatide, survodutide, lanifibranor, pegozafermin, and resmetirom demonstrate substantial promise in resolving MASH and improving fibrosis, but unresolved issues remain regarding treatment duration, response heterogeneity, and long-term adherence. Genetic variants (e.g., PNPLA3 polymorphisms) and emerging molecular biomarkers may enhance stratification, while artificial intelligence is beginning to shape trial design and drug development. As the field moves toward combination therapies and precision medicine, the definition of therapeutic success will likely evolve to reflect both histological improvement and patient-reported outcomes. This Review provides a timely synthesis of the landscape, challenges, and future directions in MASH therapeutics.
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