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.

Copper is essential for mitochondrial respiration, antioxidant defense, extracellular matrix maturation, and cellular signaling, yet disturbances in its abundance or intracellular distribution can damage the kidney through mechanistically distinct pathways. Cuproptosis is a specific copper-dependent form of regulated cell death in which copper binds lipoylated mitochondrial proteins, promotes aggregation of tricarboxylic acid cycle components, destabilizes iron–sulfur cluster proteins, and elicits FDX1- and protein lipoylation-dependent proteotoxic stress. This mechanism should be distinguished from broader copper-associated injury, including redox imbalance, glutathione depletion, respiratory-chain inhibition, senescence, apoptosis, and lysyl oxidase-mediated matrix remodeling. This narrative review examines how renal copper uptake, trafficking, and compartmentalization interact with cell-specific metabolism to shape copper-related cell fates across acute kidney injury, nephrotoxicity, renal ischemia–reperfusion injury, crystal- and lipid-related tubular injury, diabetic kidney disease, podocyte injury, chronic kidney disease and renal fibrosis, end-stage renal disease, renal cell carcinoma, and hereditary copper disorders. Mechanistic evidence is strongest in selected acute tubular, crystal-injury, and renal cancer models, in which transporter manipulation, DLAT oligomerization, iron–sulfur perturbation, or functional rescue has been demonstrated. In chronic kidney disease and fibrosis, copper-DLAT interactions, complex IV inhibition, COMMD1-SOD1 dysfunction, and ATP7A-FBLN4-LOX signaling establish pathogenic copper dependence but do not yet demonstrate a complete canonical cuproptosis pathway. By integrating disease-specific evidence with the molecular determinants of copper handling and protein lipoylation, this review identifies current therapeutic opportunities, candidate biomarkers, and key research priorities while preserving the distinction between cuproptosis and other forms of copper-associated kidney injury.