Epigenetic regulation in cardiac fibrosis: From mechanisms to therapeutic strategies

Cardiac fibrosis is a common and critical pathological process underlying a wide range of cardiovascular diseases and remains a major unmet therapeutic challenge. Emerging evidence indicates that epigenetic modifications, including DNA methylation, histone modifications, RNA modifications, and non-coding RNAs, play critical roles in regulating fibroblast activation, extracellular matrix (ECM) deposition, and cardiac remodeling. Beyond their mechanistic importance, these epigenetic regulators represent promising and druggable targets for anti-fibrotic therapy. Increasing evidence, primarily from preclinical studies, demonstrates that targeting key epigenetic enzymes and pathways, such as DNA methyltransferases (DNMTs), histone deacetylases (HDACs), bromodomain and extra-terminal (BET) proteins, and N 6 -methyladenosine (m 6 A) regulators, can effectively modulate fibrotic signaling. This review provides a comprehensive and integrative overview of the epigenetic mechanisms underlying cardiac fibrosis, with a particular focus on the druggability, mechanisms of action, and translational potential of key epigenetic regulators. We summarize current epigenetic therapeutic strategies, including representative drugs, their molecular targets, and the supporting evidence from preclinical studies to early-phase clinical trials. We also discuss key challenges, including target specificity, delivery strategies, and clinical translation. By bridging epigenetic mechanisms with drug development, this review highlights the potential for precision anti-fibrotic therapies and provides a framework for future translational research.