Mechanism of Semaglutide in MASLD Treatment: Where Is the Master Key?

BACKGROUND: Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), is used for weight reduction and metabolic improvement. Semaglutide effectively improves MASH but not confers histological fibrosis resolution. The key question remains whether semaglutide exerts direct, independent effects in ameliorating MASH or if its benefits are merely secondary to improvements in weight, insulin resistance, and glycemic control. The exact mechanisms of action through which semaglutide or other GLP-1 RAs offer liver protection are not entirely clear. METHODS: A comprehensive search in PubMed and EMBASE was conducted using the keywords "Semaglutide and NAFLD/MASLD", "glucagon-like peptide-1 receptor agonist and MASLD/NALFD", and "Semaglutide and type II diabetes/obesity and hypertension". Relevant papers published before February, 2025, were included. RESULTS: Semaglutide modulates several lipid-associated molecular pathways through unknown mechanisms. Preclinical and clinical studies suggest that semaglutide acts by (i) reducing appetite and increasing satiety, thereby decreasing dietary intake and subsequent free fatty acid export to the liver; (ii) reducing insulin resistance and improving insulin sensitivity and adipose dysfunction; (iii) reducing de novo lipogenesis by downregulating ChREBP and SREBP-1c signaling, as well as the expression of lipid-synthesizing genes; (iv) reducing the weight of white and brown adipose tissue; and (v) reducing inflammation by decreasing pro-inflammatory markers in GLP-1-expressing macrophages and favorably altering the gut microbiota. CONCLUSION: While this review explores the potential mechanisms of semaglutide action, the lack of GLP-1 receptor expression in the livers of mice and humans suggests that these mechanisms are associated with indirect modulation. Consequently, further mechanistic studies are needed to elucidate these pathways. TRIAL REGISTRATION: NOT APPLICABLE.