Epigenetics in Atrial Fibrillation: Molecular Mechanisms and Therapeutic Avenues

Atrial fibrillation (AF) represents the most common sustained cardiac arrhythmia in clinical practice and imposes a growing global disease burden. However, current therapeutic strategies remain considerably limited in efficacy, durability, and safety. Recently, the role of epigenetic mechanisms in the pathogenesis of AF, as key regulators of atrial structural and electrical remodeling, has garnered considerable attention. This review systematically elucidates the central role of multiple epigenetic regulatory mechanisms, including deoxyribonucleic acid (DNA) methylation, histone modifications, non-coding ribonucleic acids (RNAs) (microRNAs, long non-coding RNAs, circular RNAs, and transfer RNA-derived small RNAs), chromatin remodeling, and RNA methylation, in the atrial structural and electrical remodeling underlying AF. These reversible molecular modifications are widely implicated in the pathophysiological processes of AF through the regulation of key gene expression. In addition, circulating epigenetic markers (e.g., methylated DNA fragments and specific miRNAs) show substantial potential as biomarkers for AF diagnosis, risk stratification, and relapse prediction. Furthermore, targeted epigenetic intervention strategies (e.g., histone deacetylase (HDAC) inhibitors, demethylating agents) offer novel avenues for the precision therapy of AF. Thus, this review seeks to comprehensively summarize recent advances in the epigenetic regulation of AF pathogenesis, provide a theoretical basis for an in-depth understanding of the underlying mechanisms, and inform the development of innovative preventive and therapeutic strategies.