Epigenetic Regulation of Liver Fibrosis: Mechanisms and Therapeutic Implications

Abstract

Liver fibrosis is a common consequence of chronic liver injury and a major contributor to liver‐related mortality. Persistent hepatocellular injury promotes fibrosis initiation and progression through excessive extracellular matrix deposition. Hepatic stellate cells (HSCs), the principal source of extracellular matrix in the fibrotic liver, transition from a quiescent state to an activated myofibroblast‐like phenotype in response to profibrotic stimuli such as transforming growth factor‐beta. This transition is accompanied by transcriptional and epigenetic reprogramming involving DNA methylation, histone modifications, and regulation by non‐coding RNAs. Treating the underlying cause of liver disease, such as promoting weight loss in metabolic dysfunction‐associated steatohepatitis or eradicating viral hepatitis, remains the principal strategy for slowing or potentially reversing fibrosis. Despite substantial advances in understanding the cellular and molecular basis of liver fibrosis and HSC activation, most mechanism‐based therapeutic approaches have not yet demonstrated clinical efficacy. Further translational and clinical studies are therefore required. Recent advances in molecular biology have highlighted the potential relevance of epigenetic modifications to the diagnosis, treatment, and prognosis of chronic liver disease. In this review, we summarize the principal epigenetic changes involved in HSC activation, and initiation/progression of liver fibrosis. We also discuss recent interventions designed to modulate these epigenetic changes and evaluate their therapeutic potential in experimental models of liver fibrosis.