GLP-1 receptor agonists in metabolic dysfunction-associated steatotic liver disease: mechanistic networks and translational implications: a review.

AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent worldwide and may progress to metabolic dysfunction-associated steatohepatitis (MASH), advanced fibrosis, cirrhosis, and hepatocellular carcinoma, yet effective pharmacological therapies remain limited. This review summarizes current evidence on the therapeutic potential and mechanistic basis of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in MASLD. METHODS: We synthesize findings from preclinical models and clinical studies evaluating GLP-1RAs in MASLD/MASH, with emphasis on hepatic metabolic pathways, inflammatory and fibrogenic signaling, and gut-liver axis mechanisms, as well as outcomes from clinical trials and emerging multi-agonist strategies. RESULTS: Clinical studies support the therapeutic relevance of GLP-1RAs in MASLD/MASH by demonstrating reductions in liver fat content, improvements in liver enzyme profiles, and favorable histologic changes, particularly with semaglutide and emerging multi-agonist therapies in selected populations. Preclinical and translational studies further suggest that these benefits may be mediated through integrated effects on hepatic lipid handling, oxidative and inflammatory stress, fibrogenic signaling, and the gut-liver axis, although the relative contribution of direct hepatic versus indirect systemic mechanisms remains incompletely resolved. CONCLUSIONS: Current evidence supports an expanding role for GLP-1-based therapies in metabolic liver disease and provides a mechanistic framework for their continued development and clinical evaluation in MASLD.