Iron and Copper Homeostasis in Cardiometabolic Disease: Therapeutic Potential of Chelators.

Cardiometabolic diseases remain a leading global health burden, and growing evidence indicates that dysregulation of iron and copper homeostasis plays a central role in their pathogenesis. Two metal-dependent forms of regulated cell death-ferroptosis and cuproptosis-have recently emerged as key mechanisms linking redox imbalance, mitochondrial dysfunction, vascular injury, and metabolic deterioration. This review synthesizes current mechanistic knowledge on iron- and copper-mediated cell death, with emphasis on their convergence at shared metabolic vulnerabilities, including glutathione depletion, instability of iron-sulfur clusters, and tricarboxylic acid cycle dependence. We integrate insights from single-cell transcriptomics, lipidomics, and metallomics with machine-learning-derived gene signatures to highlight novel biomarkers and vulnerability nodes relevant to coronary artery disease, myocardial infarction, heart failure, atherosclerosis, and diabetic complications. Special focus is placed on the therapeutic potential of metal chelators and metal-targeting pharmacological strategies, including mitochondria-directed copper depletion, iron chelation, radical-trapping antioxidants, copper ionophores, and dual-action approaches capable of rebalancing both metals simultaneously. Innovative delivery systems, such as targeted nanocarriers and copper-modulating microbubbles, are discussed in the context of precision redox medicine. Despite rapid progress, translation remains limited by biomarker variability, systemic safety concerns, and the lack of large, prospective clinical trials. Overall, the review positions the iron-copper axis as a mechanistically unified and therapeutically tractable target, offering new perspectives for the development of chelators and metal complexes in cardiometabolic disease management.