GLP-1 receptor agonists show therapeutic potential for MASLD by improving liver fat, enzymes, and histology

Effective pharmacological therapies for Metabolic dysfunction-associated steatotic liver disease (MASLD), which can progress to Metabolic dysfunction-associated steatohepatitis (MASH), advanced fibrosis, cirrhosis, and hepatocellular carcinoma, remain severely limited. The global epidemics of obesity and type 2 diabetes have driven a significant increase in MASLD prevalence, underscoring an urgent need for new treatments. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are being investigated due to their established metabolic benefits and emerging evidence of hepatic improvements.

This comprehensive review synthesizes findings from both preclinical models and clinical studies evaluating GLP-1RAs in MASLD/MASH. The authors emphasized key mechanistic networks, including hepatic metabolic pathways, inflammatory and fibrogenic signaling, and the intricate gut-liver axis. The review also critically assessed outcomes from existing clinical trials and explored the potential of emerging multi-agonist strategies, providing a detailed overview of the current evidence base for GLP-1-based therapies.

Clinical studies consistently support the therapeutic relevance of GLP-1RAs in MASLD/MASH, demonstrating significant reductions in liver fat content, improvements in liver enzyme profiles, and favorable histologic changes. These benefits are particularly notable with semaglutide and emerging multi-agonist therapies in selected patient populations. Preclinical and translational studies further suggest that these positive outcomes are mediated through integrated effects on several key pathways. These include improved hepatic lipid handling, reduced oxidative and inflammatory stress, modulation of fibrogenic signaling, and beneficial interactions within the gut-liver axis. However, the precise relative contribution of direct hepatic versus indirect systemic mechanisms remains incompletely resolved, indicating an area for further research. GLP-1RAs consistently reduce liver fat content, improve liver enzyme profiles, and induce favorable histologic changes in MASLD/MASH patients.