Repurposing GLP-1 Receptor Agonists: A Perspective on Epigenetic Strategies to Combat Fibrosis and Hepatocellular Carcinoma in the Aged Liver.

The liver's susceptibility to age-related diseases, including hepatocellular carcinoma (HCC), is increasingly linked to progressive epigenetic alterations that disrupt gene regulation, promote fibrosis, and impair regeneration. While glucagon-like peptide-1 receptor agonists (GLP-1RAs) are well-established in the treatment of type 2 diabetes and obesity, emerging evidence suggests they may also exert protective effects on the liver through the modulation of epigenetic pathways. In this perspective, we explore the hypothesis that GLP-1RAs may help restore a healthier epigenetic state in the aging liver by influencing mechanisms such as DNA methylation, histone modification, and non-coding RNA activity. These effects could reduce chronic inflammation, hepatic stellate cell activation, and fibrotic remodeling, key steps in the path to HCC. Preclinical studies have shown GLP-1RAs can affect transcriptional regulation and fibrotic markers, and early clinical data support improvements in liver function and structure in patients with metabolic liver disease. We highlight the need for further research to clarify these mechanisms in aging populations and propose that GLP-1RAs hold potential as a novel therapeutic strategy to reduce liver cancer risk by targeting the epigenetic contributors to disease progression.