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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\u20101 RAs offer liver protection are not entirely clear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A comprehensive search in PubMed and EMBASE was conducted using the keywords \u201cSemaglutide and NAFLD\/MASLD\u201d, \u201cglucagon\u2010like peptide\u20101 receptor agonist and MASLD\/NALFD\u201d, and \u201cSemaglutide and type II diabetes\/obesity and hypertension\u201d. Relevant papers published before February, 2025, were included.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Semaglutide modulates several lipid\u2010associated 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 <jats:italic>de novo<\/jats:italic> lipogenesis by downregulating ChREBP and SREBP\u20101c signaling, as well as the expression of lipid\u2010synthesizing genes; (iv) reducing the weight of white and brown adipose tissue; and (v) reducing inflammation by decreasing pro\u2010inflammatory markers in GLP\u20101\u2010expressing macrophages and favorably altering the gut microbiota.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>While this review explores the potential mechanisms of semaglutide action, the lack of GLP\u20101 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.<\/jats:p><\/jats:sec><jats:sec><jats:title><jats:bold>Trial Registration:<\/jats:bold> Not applicable<\/jats:title><\/jats:sec>","DOI":"10.1111\/jgh.17037","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T01:04:32Z","timestamp":1750381472000},"page":"2163-2175","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Mechanism of Semaglutide in MASLD Treatment: Where Is the Master Key?"],"prefix":"10.1111","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5068-2383","authenticated-orcid":false,"given":"Devaraj","family":"Ezhilarasan","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Hepatology and Molecular Medicine Lab Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS)  Chennai Tamil Nadu 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