Role of Copper Homeostasis and Cuproptosis in Cardiovascular Disease: Molecular Insights and Metabolic Perspectives

Copper is an essential trace element; however, its homeostasis is frequently disrupted in cardiovascular diseases, which are a leading cause of mortality worldwide. The recent discovery of cuproptosis-a copper-dependent form of regulated cell death (RCD)-has provided a crucial mechanistic link between this imbalance and cardiomyocyte loss. In this review, we synthesize the current understanding of how dysregulated copper metabolism and cuproptosis drive the pathogenesis of major cardiovascular conditions, including myocardial ischemia/reperfusion (I/R) injury, anthracycline-induced cardiotoxicity, atherosclerosis, diabetic cardiomyopathy (DCM), and sepsis-induced cardiac dysfunction, through pathways such as mitochondrial dysfunction, oxidative stress, and inflammation. We further evaluated emerging therapeutic strategies that target copper homeostasis-including chelators, chaperone inhibitors, and ionophores-and critically analyzed the translational challenges they face, such as off-target effects and preclinical model limitations. Advancing our knowledge of cardiac copper biology holds significant promise for the development of novel and precise therapeutic approaches for cardiovascular diseases.