GLP-1 RAs for Treating Metabolic Dysfunction-Associated Steatosis Liver Disease: From GLP-1 Discovery to FDA Approval: A Comprehensive Narrative Review

<b>Background:</b> Metabolic dysfunction-associated steatosis liver disease (MASLD), formerly termed nonalcoholic fatty liver disease (NAFLD), has emerged as the most prevalent cause of chronic liver disease worldwide. For decades, the absence of approved pharmacological therapies has hindered effective clinical management, leaving lifestyle modification and sustained weight reduction as the only recommended interventions. Yet, achieving and maintaining clinically meaningful weight loss remains an enduring challenge for most patients. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally established as cornerstone therapies for type 2 diabetes (T2D) and obesity, have recently gained FDA approval for MASLD. Extensive mechanistic, preclinical, and clinical evidence demonstrates their ability to reduce hepatic steatosis, attenuate inflammatory pathways, and impede disease progression, establishing GLP-1RAs as the first pharmacological class with robust, multi-level efficacy in MASLD. <b>Scope of review:</b> This review synthesizes the evidence-based knowledge that led to the approval of GLP-1RAs for MASLD management. Integrating findings from (A) in vitro hepatocellular and multicellular models, (B) established animal models of steatosis-induced liver injury, and (C) clinical trials in patients with MASLD and its inflammatory subtype. We also discuss current limitations, unresolved questions, and future research priorities to optimize the therapeutic potential of GLP-1RAs in MASLD.