Emerging roles of cuproptosis in liver diseases

Intracellular copper levels should be maintained within a controlled range to obtain copper homeostasis. Cuproptosis, a newly discovered form of cell death, occurs when excessive copper ions bind to the lipoylated enzymes in the tricarboxylic acid cycle, which leads to lipoylated protein aggregation, proteotoxic stress, and ultimately cell death. Herein, we summarize the current knowledge regarding copper metabolism, the discovery and molecular mechanism of cuproptosis. In addition, we discuss the implications of cuproptosis in the pathogenesis of various liver diseases, including hepatocellular carcinoma (HCC), Wilson disease (WD), metabolic-associated fatty liver disease (MAFLD), liver fibrosis, hepatic ischemia-reperfusion injury (HIRI) and drug-induced liver injury (DILI). Understanding the mechanism of cuproptosis can not only provide deeper insights into the pathogenesis of liver diseases but also open up new avenues for the development of targeted therapies.