Epigenetic Regulatory Networks in Cardiac Fibrosis: Therapeutic Targets, Crosstalk, and Future Directions

Abstract: Cardiac fibrosis is a central driver of pathological cardiac remodeling and a critical risk factor for the progression to heart failure. Cardiac fibrosis may induce myocardial ischemia and hypoxia, impaired cardiac function, and arrhythmias, and is thereby intimately linked to escalating cardiac mortality. Epigenetic mechanisms serve as core drivers in both the initiation and malignant evolution of cardiac fibrosis. Currently, the epigenetic regulatory network primarily covers five cutting-edge domains: (1) dynamic DNA methylation modifications, (2) the histone post-translational modifications, (3) emerging RNA epitranscriptomic modifications, (4) the non-coding RNA regulatory network, and (5) ATP-dependent chromatin remodeling. This review moves beyond conventional pathological frameworks to examine the multi-layered synergistic actions of epigenetic regulation in cardiac fibrosis. By deconstructing the specific spatiotemporal expression profiles of these dynamic modification mechanisms, we systematically evaluate their translational potential as reversible interventional targets, offering a critical synthesis of these epigenetic mechanisms and pointing to plausible research directions for overcoming fibrotic progression toward heart failure. Keywords: cardiac fibrosis, epigenetic regulation, RNA epitranscriptomic modifications, therapeutic targets