Metabolic underpinnings of cuproptosis

Cuproptosis is a recently defined form of regulated cell death (RCD) driven by copper-induced mitochondrial proteotoxic stress. Distinct from other RCD pathways such as apoptosis and ferroptosis, cuproptosis arises when copper binds to lipoylated metabolic enzymes in mitochondria, leading to their aggregation, loss of iron-sulfur cluster proteins, and metabolic collapse. This discovery establishes a mechanistic link between metal homeostasis and mitochondrial metabolism, positioning cuproptosis as a "cell-sabotage" pathway in which essential metabolic processes become self-destructive when dysregulated. In this review, we synthesize recent advances in understanding the molecular and metabolic basis of cuproptosis, its intersection with other metabolic cell death pathways such as ferroptosis, and its emerging therapeutic relevance in cancer. We further discuss the potential involvement of cuproptosis-like mechanisms in neurodegenerative disorders and highlight the outstanding questions and translational challenges that will guide future efforts to exploit this unique metabolic vulnerability for disease intervention.