The dual functionality of EZH2 in cardiovascular disease: Bridging cancer biology and cardiac pathophysiology through epigenetic regulation, metabolic reprogramming, and novel therapeutic interventions.

Enhancer of zeste homolog 2 (EZH2), canonically recognized as an oncogenic driver through its histone methyltransferase activity, has emerged as a critical epigenetic orchestrator in cardiovascular pathophysiology with unexpected functional complexity. While extensive oncological research has established EZH2's role in facilitating the Warburg effect and metabolic reprogramming in cancer cells, recent cardiovascular investigations reveal that EZH2 employs remarkably parallel mechanisms to coordinate the metabolic shift from oxidative phosphorylation to glycolysis during cardiac ischemia-a previously unrecognized molecular paradigm bridging cancer biology and cardiovascular pathophysiology. This review synthesizes emerging evidence demonstrating EZH2's unique context-dependent functionality in cardiac tissue, acting simultaneously as a transcriptional co-activator through non-canonical FOXM1 interaction and as an epigenetic repressor via its canonical PRC2-mediated H3K27 trimethylation activity. Most significantly, we highlight the novel discovery that EZH2 establishes a distinctive methylation landscape in ischemic cardiomyopathy through direct interaction with DNA methyltransferases, creating a molecular signature that suppresses cardioprotective factors like KLF15 while enhancing matrix metalloproteinase expression that drives adverse cardiac remodeling. Despite compelling preclinical evidence supporting EZH2 inhibition across multiple cardiovascular conditions, including atherosclerosis, cardiac hypertrophy, and myocardial fibrosis, a critical translational gap persists due to delivery limitations, potential off-target effects, and inadequate understanding of EZH2's temporal and tissue-specific functions. This review identifies crucial research opportunities, including developing cardiac-specific EZH2 modulators, exploring combination therapies targeting downstream pathways, and comprehensive interactome mapping to reveal cardiovascular-specific interactions. Decoding the complex regulatory networks governed by EZH2 across developmental stages and disease contexts represents a frontier for developing innovative epigenetic interventions addressing the global burden of cardiovascular disease.