Iron, Copper, and Zinc Dyshomeostasis in Cardiovascular and Cerebrovascular Diseases: Redox Mechanisms, Evidence Levels, and Translational Prospects.

Iron (Fe), copper (Cu), and zinc (Zn) are essential trace elements for cardiovascular and cerebrovascular homeostasis, acting as enzymatic cofactors in energy metabolism and antioxidant defence. However, disruption of metal homeostasis can amplify oxidative injury through direct Fe/Cu redox chemistry or indirect Zn-dependent pathways. Ferroptosis and cuproptosis have been investigated as context-dependent mechanisms in various cardiovascular and cerebrovascular diseases (CCVDs), such as atherosclerosis, ischaemic/haemorrhagic stroke, diabetic vascular disease, and abdominal aortic aneurysm. This review summarizes the physiological regulation of metal homeostasis and examines pathways through which metal dyshomeostasis may contribute to vascular and neural injury, including oxidative biomolecular modification, mitochondrial dysfunction and inflammatory signalling. It further summarizes therapeutic strategies targeting metal metabolism, such as metal chelators, trace element supplementation and nanomedicine-based targeted delivery systems, which have shown protective effects predominantly in experimental models by restoring metal homeostasis and scavenging reactive oxygen species. Finally, the review highlights key challenges in clinical translation, such as tissue-specific metal detection and targeted inhibitor development, and emphasizes that precise regulation of metal metabolism may offer therapeutic opportunities for CCVDs.