Copper-Induced Cell Death in Renal Diseases: Molecular Mechanisms and Therapeutic Implications.

Copper dyshomeostasis and the resulting induction of cuproptosis, a novel regulated cell death pathway driven by mitochondrial copper overload, play a critical role in renal pathophysiology. Cuproptosis is characterized by FDX1-mediated copper reduction, irreversible aggregation of lipoylated TCA cycle enzymes, such as dihydrolipoamide S-acetyltransferase, and destabilization of iron‒sulfur cluster proteins, leading to proteotoxic mitochondrial collapse. The kidney's high vulnerability arises from its filtration and metabolic functions. This review consolidates evidence linking cuproptosis to various renal disorders, including acute kidney injury (eg, sepsis-induced, cisplatin-induced, and ischemia-reperfusion injury), diabetic nephropathy through mitochondrial dysfunction and immune dysregulation, and chronic kidney disease involving podocyte damage or context-dependent dysregulation in fibrosis and clear cell renal cell carcinoma. Notably, cuproptosis and ferroptosis interact synergistically through shared mechanisms, where glutathione depletion or iron overload exacerbates both pathways, while mitochondrial dysfunction and lipid peroxidation create a self-perpetuating injury cycle. Emerging diagnostic strategies utilize cuproptosis-related biomarkers for early detection, supported by various prediction models. In therapeutic contexts, copper chelators, transporter modulators, and dual-pathway inhibitors targeting both cuproptosis and ferroptosis mitigate renal damage in preclinical models. Dietary interventions that modulate copper bioavailability also hold promise. However, challenges remain, including identifying renal cell type-specific mechanisms, developing noninvasive biomarkers, optimizing kidney-targeted nanotherapeutics, and preventing iatrogenic copper deficiency. Future research may focus on translational applications and the physiological roles of cuproptosis in renal repair. Targeting cuproptosis offers a promising avenue for innovative diagnostics and treatments in nephrology.