The epigenetic roles of pirfenidone - implication in liver disease management

Liver diseases represent a major global health challenge, responsible for over two million deaths annually. Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are the primary contributors to liver fibrosis and hepatocarcinoma (HCC). Epigenetic mechanisms, including DNA methylation, histone modifications, and miRNAs, play a crucial role in the pathogenesis of liver disorders, presenting promising therapeutic targets due to their reversibility. Pirfenidone, an antifibrotic agent approved for idiopathic pulmonary fibrosis (IPF) and hepatic fibrosis in Mexico, has shown significant potential to modulate epigenetic pathways. This review discusses the molecular and epigenetic mechanisms by which PFD exerts hepatoprotective effects, including modulation of miRNA expression, restoration of DNA methylation patterns, and regulation of histone acetylation and methylation. Notable findings include PFD-mediated downregulation of pro-fibrotic miRNAs, hypermethylation of TGFB1, and inhibition of JMJD2B histone demethylase. Together, these findings suggest that PFD not only targets fibrotic and inflammatory pathways but also acts as a novel epigenetic regulator, positioning it as a promising therapeutic candidate for MASLD, MASH, and HCC.