Enhancer of Zeste Homolog 2 (EZH2) has traditionally been recognized as a pivotal oncogenic driver through its histone methyltransferase activity that promotes aberrant gene silencing in multiple cancer types.1,2 However, an emerging body of evidence has dramatically expanded our understanding of this epigenetic regulator beyond oncology, revealing its critical and multifaceted roles in cardiovascular pathophysiology. Initially characterized as the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) that orchestrates H3K27 trimethylation and subsequent transcriptional repression, EZH2 has now been identified as a sophisticated molecular switch capable of both repressing cardioprotective pathways and activating maladaptive programs in cardiac tissue3 This functional duality serves as both a transcriptional co-activator through non-PRC2 mechanisms and an epigenetic repressor via its canonical histone methyltransferase activity, positioning EZH2 at the crossroads of cardiac homeostasis and disease progression. Particularly intriguing is the parallel between EZH2′s well-established role in cancer metabolism and its emerging function in cardiac metabolism during ischemia, where it appears to facilitate a fundamental shift from oxidative phosphorylation to glycolysis reminiscent of the Warburg effect observed in malignancies.

Cardiovascular diseases (CVDs) represent one of the most formidable challenges in global healthcare, exhibiting elevated prevalence, significant disability burden, and high mortality rates worldwide 4 The World Health Organization's 2017 World Health Statistics Report revealed that in 2015 alone, CVDs were responsible for an estimated 17.7 million fatalities globally, constituting approximately 44 % of all deaths. Notably, the European region suffered disproportionately, with CVD contributing to more than half of all recorded mortalities in this area.5, 6, 7 Despite considerable progress in therapeutic interventions that have enhanced patients' quality of life, the incidence and fatality rates associated with CVDs continue their upward trajectory, correlating strongly with societal advancement and contemporary lifestyle modifications. This trend underscores the need to identify and develop novel therapeutic targets and approaches.

Vascular smooth muscle cells (VSMCs), primarily within blood vessel walls, play a fundamental role in maintaining vascular homeostasis through regulating vascular tone and contractility.8,9 When subjected to vascular injury or exposed to various bioactive compounds—including nitric oxide derivatives, angiotensin II (Ang II), and platelet-derived growth factors—VSMCs undergo proliferation and migration processes.10,11 These cellular responses constitute critical mechanisms underlying pathological vascular transformations, including vessel wall thickening, luminal narrowing, and adverse vascular remodeling. The remarkable phenotypic plasticity of VSMCs enables their adaptation to diverse environmental conditions, significantly influencing the pathogenesis and progression of atherosclerosis 12 During episodes of vascular damage and inflammatory responses, VSMCs proliferate and migrate strategically to establish a protective fibrous cap. However, these cells infiltrate the plaque core, paradoxically accelerating atherosclerotic progression. The phenotypic state of VSMCs, substantially modulated by the surrounding immune microenvironment, therefore represents a critical determinant in the etiology of AS and related cardiovascular pathologies.

Further complicating the pathophysiological landscape, VSMC apoptosis destabilizes the fibrous cap and plaque structures, triggering calcification processes and activating the immune system 13 These mechanisms collectively exacerbate AS development and progression. Beyond atherosclerosis, dysregulated VSMC proliferation, migration, and programmed cell death are implicated in numerous other cardiovascular conditions, including hypertension, aortic dissection, aortic aneurysm (AA), and coronary heart disease. These observations collectively emphasize the pivotal importance of VSMCs in CVD pathophysiology and offer valuable perspectives for developing targeted therapeutic interventions14 The epigenetic landscape regulated by EZH2 represents a complex but promising frontier in cardiovascular medicine. Unlike genetic mutations, epigenetic modifications are potentially reversible, offering unique therapeutic opportunities15 EZH2-mediated histone methylation influences chromatin accessibility, determining which genes remain accessible to transcriptional machinery. In the context of VSMCs, this epigenetic control affects genes regulating proliferation, migration, inflammation, and phenotypic switching, all critical processes in CVD pathogenesis.

Consequently, a comprehensive elucidation of the molecular mechanisms underlying EZH2-mediated regulation of VSMC function in cardiovascular pathologies is essential for developing innovative therapeutic strategies. This review explores the rapidly evolving paradigm of EZH2 as a master epigenetic regulator across the cardiovascular disease spectrum, highlighting its mechanistic complexity and therapeutic potential.