Cuproptosis in kidney diseases: Mechanisms, pathophysiology, and therapeutic implications

Cuproptosis is a copper-dependent form of regulated cell death characterized by copper binding to lipoylated mitochondrial proteins, protein aggregation, loss of iron–sulfur cluster proteins, and proteotoxic stress. This review examines the molecular mechanisms of cuproptosis, its involvement in acute kidney injury (AKI), chronic kidney disease (CKD), diabetic nephropathy (DN), and renal cell carcinoma (RCC), and the therapeutic implications of its modulation. Experimental studies implicate cuproptosis in tubular epithelial injury, podocyte dysfunction, and renal damage associated with metabolic, ischemic, and inflammatory stress. In clear cell RCC, altered expression of cuproptosis-related genes is associated with tumor behavior, prognosis, and the immune microenvironment, while experimental induction of copper-dependent cell death provides a rationale for therapeutic investigation. These findings support a disease-dependent approach: suppressing cuproptosis to protect non-malignant renal tissue and inducing it to target susceptible cancer cells. Copper chelators, copper ionophores, and interventions targeting pathway regulators are being investigated within this framework. However, much of the evidence derives from computational analyses and preclinical models, and gene-expression signatures alone do not establish active cuproptosis. Clinical translation requires functional validation, reliable biomarkers, and strategies that achieve tissue selectivity while preserving essential copper homeostasis. Cuproptosis therefore provides a mechanistic framework for investigating renal injury and cancer, with therapeutic application dependent on establishing efficacy and safety in the relevant disease context.