Apoptosis. 2026 Jul 01. pii: 180. [Epub ahead of print]31(7):
Copper is an essential micronutrient required for mitochondrial respiration, antioxidant defense, and metabolic homeostasis. Accumulating evidence demonstrates that dysregulated copper handling, including deficiency, redistribution, or overload, is a reproducible feature of multiple cardiometabolic disorders, including heart failure, diabetes mellitus, obesity, and NAFLD/MASLD. Human, animal, and cellular studies consistently implicate altered copper trafficking and compartmentalization in mitochondrial dysfunction, oxidative stress, and tissue remodeling across these conditions. The recent identification of cuproptosis, a copper-dependent form of regulated cell death characterized by mitochondrial copper binding to lipoylated tricarboxylic acid cycle enzymes, has expanded mechanistic understanding of copper toxicity in cancer. However, the defining molecular hallmarks of canonical cuproptosis, including lipoylated protein aggregation, iron-sulfur cluster loss, and respiration-dependent cell death, have not yet been demonstrated in vivo in cardiometabolic tissues. Accordingly, cuproptosis is discussed here as a testable mechanistic hypothesis rather than an established driver of cardiometabolic pathology. In this review, we synthesize current evidence for copper dysregulation in cardiometabolic disease and carefully distinguish established copper-dependent pathology from speculative cuproptotic mechanisms. We explicitly address the apparent paradox that the cardiac tissue context in cardiometabolic disease is dominated by a copper-deficient phenotype, which is the opposite of the mitochondrial copper-loading state required for canonical cuproptosis, and reconcile this through the concept of intracellular copper redistribution and tissue-selective susceptibility. We evaluate clinical and preclinical studies of copper-modulating therapies with attention to tissue specificity and safety, and we outline a framework for rigorously testing cuproptosis in vivo using convergent molecular, functional, and clinical criteria. Together, this review clarifies what is known about copper biology in metabolic disease and defines the experimental standards required to determine whether cuproptosis contributes to these conditions.
Keywords: Copper chelation therapy; Heart failure; Iron-sulfur cluster proteins; Lipoylated enzymes; Metabolic syndrome; Oxidative stress biomarkers