GLP-1 Receptor Agonists Show Multifunctional Therapeutic Potential Across Steatotic Liver Disease Spectrum

The global burden of steatotic liver disease (SLD), encompassing metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and metabolic dysfunction and alcohol-associated liver disease (MetALD), is rapidly increasing, driving a surge in hepatocellular carcinoma (HCC). Regardless of etiology, progression to advanced SLD and HCC is governed by shared pathways of systemic metabolic dysregulation and inflammation. There is an urgent unmet need for a single, targeted pharmacological agent that can address this unified pathophysiology, as current standard-of-care often falls short in comprehensive disease management.

This comprehensive review analyzed the epidemiological links and shared metabolic pathophysiology across various steatotic liver disease (SLD) etiologies, including MASLD, ALD, and MetALD, and their progression to hepatocellular carcinoma (HCC). Researchers synthesized existing clinical and preclinical data to evaluate the emerging potential of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as a multifunctional therapeutic strategy. The review specifically dissected their dual central and peripheral mechanisms, anti-inflammatory, and potential anti-cancer effects by examining their impact on key metabolic sensors and proliferative signaling pathways.

GLP-1 receptor agonists (GLP-1 RAs) exert a dual central and peripheral mechanism against SLD progression. Centrally, these agents effectively modulate appetite and reduce the intake and cravings for high-calorie food and alcohol. Peripherally, GLP-1 RAs induce significant weight loss, enhance insulin sensitivity, and reduce hepatic de novo lipogenesis. While their efficacy in resolving metabolic dysfunction-associated steatohepatitis (MASH) is 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 consistently support the efficacy of GLP-1 RAs in resolving steatosis and slowing 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.