Therapeutic horizons in metabolic dysfunction-associated steatohepatitis.
This review paper provides a comprehensive overview of the current and emerging pharmacological landscape for metabolic dysfunction-associated steatohepatitis (MASH), the progressive inflammatory form of metabolic dysfunction-associated steatotic liver disease (MASLD). The authors describe MASH as a growing global health burden, closely tied to obesity and type 2 diabetes, and carrying significant risks of cirrhosis, hepatocellular carcinoma, and liver failure. The review synthesizes evidence from advanced-stage clinical trials evaluating several therapeutic classes, including incretin-based therapies (GLP-1 receptor agonists, dual, and triple agonists such as semaglutide, tirzepatide, and survodutide), metabolic modulators (PPAR agonists like lanifibranor, FGF21 analogues like pegozafermin, and thyroid hormone receptor-beta agonists like resmetirom), and novel agents such as fatty acid synthase inhibitors. The authors note that regulatory endpoints currently rely on histological assessment, while noninvasive biomarkers and personalized approaches are gaining traction. Genetic factors, such as PNPLA3 polymorphisms, and artificial intelligence are highlighted as emerging tools for patient stratification and trial design. Key limitations acknowledged include unresolved questions about treatment duration, response heterogeneity, long-term adherence, and the evolving definition of therapeutic success.
Why this grade: This is a narrative review article synthesizing existing trial data and literature rather than generating primary experimental or clinical data, so it is graded as a review rather than direct human evidence.
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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