Epigenetic regulation in atherosclerosis and its therapeutic potential

Atherosclerosis is the leading cause of cardiovascular morbidity and mortality worldwide. Beyond genetic predisposition, epigenetic mechanisms, such as DNA methylation, histone modifications and non-coding RNAs, have an integral role in the development, progression and complications of atherosclerosis. Global and locus-specific changes in DNA methylation regulate cell proliferation and inflammatory activation, whereas histone post-transcriptional modifications (primarily acetylation and methylation) regulate atherosclerosis-related gene networks relevant to lipid metabolism, cell plasticity and inflammation. Long non-coding RNAs further modulate vascular remodelling by shaping cell-specific transcriptomes and guiding epigenetic enzymes and their activity, whereas microRNAs exert post-transcriptional gene regulation and non-canonical functions. In this Review, we provide an overview of epigenetic regulation in atherosclerosis, focusing on how these dynamic, reversible modifications orchestrate gene expression in vascular endothelial cells, vascular smooth muscle cells and immune cells. We highlight how technological advances and the integration of multimodal datasets have progressed this research field and describe the cell-specific contributions of genetically associated loci. Finally, we discuss preclinical study findings and the translational efforts towards the development of epigenetic drugs as promising interventions to attenuate atherosclerotic plaque progression and inflammation, shedding light on the challenges of specificity, delivery and long-term safety. Achieving clinical applicability will enable precision medicine approaches to transform atherosclerosis therapy.