Beyond diabetes and obesity: GLP-1 receptor agonists as multifunctional therapeutics across the steatotic liver disease spectrum

The global incidence of steatotic liver disease (SLD), driven by metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and the synergistic metabolic dysfunction and alcohol-associated liver disease (MetALD), is fueling a rapid rise in hepatocellular carcinoma (HCC). Regardless of the initial etiology (metabolic, alcoholic, or viral), progression to advanced SLD and HCC is governed by critical shared pathways, which are systemic metabolic dysregulation and inflammation. Identifying a single, targeted pharmacological agent to address this unified pathophysiology is an urgent unmet need. This review addresses the epidemiological links between SLD etiologies and HCC, dissecting their shared metabolic pathophysiology. We evaluate the emerging potential of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as a multifunctional therapeutic strategy to target this metabolic hepatic nexus. GLP-1 RAs offer a dual central and peripheral mechanism against SLD progression. Centrally, these GLP-1 RAs modulate appetite and reduce the intake and cravings for high-calorie food and alcohol. Peripherally, these agents induce significant weight loss, enhance insulin sensitivity, and reduce hepatic de novo lipogenesis. While their efficacy in resolving metabolic dysfunction-associated steatohepatitis (MASH) is increasingly well documented, their ability to target the metabolic hepatic nexus also suggests a promising therapeutic role in ALD and MetALD. Furthermore, GLP-1 RAs appear to exert direct anti-inflammatory and anticancer effects by activating metabolic sensors, such as the AMPK pathway, to inhibit proliferative signaling. Clinical and preclinical data support the efficacy of GLP-1 RAs in resolving steatosis and SLD progression in metabolic contexts. By targeting shared metabolic dysregulation, GLP-1 RAs emerge as potential candidates for HCC risk mitigation and may serve as future therapeutic adjuvants. Future large-scale, prospective clinical trials are warranted to confirm these benefits, particularly in ALD and MetALD, where underlying metabolic dysfunction remains a significant driver of disease progression.