A metabolic perspective on cuproptosis

Copper (Cu) is an essential trace element that plays a fundamental role in various biological processes, including electron transfer and enzymatic reactions. Cu homeostasis is tightly regulated by transporters, including CTR1 and ZnT1, that mediate Cu uptake, as well as by intracellular Cu chaperones and exporters such as ATP7A and ATP7B. Excessive accumulation of Cu can lead to cuproptosis, a form of regulated cell death characterized by Cu-induced lipoylated protein aggregation and degradation of Fe-S cluster proteins. We discuss how recent insights into Cu metabolism and cuproptosis have expanded our understanding of Cu homeostasis, and present new opportunities for the treatment of human diseases involving Cu imbalance, including Menkes and Wilson's diseases, neurodegenerative conditions, and cancer.