Methylation-centric epigenetic regulation in dilated cardiomyopathy: mechanisms, metabolic interplay, and translational potential

Dilated cardiomyopathy (DCM) is one of the main causes of heart failure and heart transplantation, with complex causes involving multiple factors such as genetics, epigenetics, and environment. In recent years, methylation, as a key epigenetic regulatory approach, has increasingly garnered attention for its role in the mechanisms of DCM onset. This review comprehensively summarizes the mechanisms, functions, and metabolic regulatory characteristics of DNA methylation, histone methylation, and RNA N6-methyladenosine (m6A) modification in the occurrence and development of DCM. Literature was selected from PubMed and Web of Science, focusing on studies related to methylation and DCM published in recent years, as well as comprehensive and well-structured review articles. Studies have shown that these three methylation modifications collectively influence the phenotypic characteristics of DCM by regulating processes such as gene expression, metabolic homeostasis, inflammatory responses, fibrosis, and cell death in cardiomyocytes. Moreover, there is cross-regulation among these modifications, which is closely related to carbon metabolism and the tricarboxylic acid cycle. Further exploration of methylation regulatory mechanisms not only helps reveal the underlying basis of DCM but also opens new directions for targeted therapy and precision medicine. This article aims to summarize existing research advancements, explore the clinical translation potential of methylation-related mechanisms, and identify key questions and challenges for future studies.