DNA/RNA Methylation-Driven Coronary Microvascular Dysfunction: Emerging Pathogenic Mechanisms and Therapeutic Opportunities for Heart Failure in Diabetes

Coronary microvascular dysfunction (CMD) is an established pathological driver of heart failure, with endothelial cell (EC) dysfunction representing a central determinant of its development and progression. EC impairment disrupts normal coronary microvascular tone and perfusion, and promotes myocardial inflammation, fibrosis, and cardiomyocyte stress, as characteristic features of the diabetic heart. CMD is often clinically silent and undiagnosed, whilst conventional therapies targeting cardiometabolic risk factors are largely ineffective towards restoring microvascular integrity. Emerging evidence implicates epigenetic dysregulation, including DNA and RNA methylation, as a critical mechanism underlying maladaptive EC signalling. These key modifications encode microvascular memory, sustaining endothelial dysfunction even after risk factors are optimally controlled; DNA methylation stabilises pathogenic transcription whilst RNA methylation regulates transcript stability and translation to support continued disruption of EC homeostasis. Indeed, preclinical studies demonstrate that pharmacological DNA methylation inhibitors and RNA methylation modulators can restore healthy EC function, reflected by reduced inflammation and preserved microvascular integrity, positioning such epigenetic pathways as central determinants of CMD with clear mechanistic relevance and therapeutic potential. Selective methylation targeting therefore offers exciting translational promise to reprogram dysfunctional ECs in diabetic patients, reversing CMD and preventing development and progression of associated heart failure. This timely review summarises current knowledge of EC epigenetic regulation, focusing on methylation modifications, and explores how emerging mechanistic insights may be leveraged to advance therapeutic targeting of CMD in the diabetic heart as foundation for development of innovative clinical management strategies.