Copper homeostasis and cuproptosis: molecular mechanisms and therapeutic opportunities

Abstract Copper, as an essential trace element, plays a critical role in various physiological processes including cell metabolism, nerve development, and immune function. Copper ions are maintained within an optimal range through a complex regulatory system in cells and organisms, ensuring dynamic equilibrium to sustain normal physiological functions and prevent copper toxicity. When this copper homeostasis is disrupted either by copper deficiency or overload, a series of pathological changes may occur, particularly in the liver, the primary organ responsible for copper metabolism. Cuproptosis is a unique form of regulated cell death specifically induced by copper ions, which has been identified mechanistically distinct from apoptosis, pyroptosis, and ferroptosis in recent research. Cuproptosis is initiated by the direct binding of copper to lipoylated proteins in the tricarboxylic acid (TCA) cycle, which leads to the aggregation of abnormal proteins, the loss of Fe-S clusters, and mitochondrial proteotoxic stress. Key regulators like the reductase FDX1 and the lipoyltransferase LIPT1 define this novel metabolic cell death pathway. As the central organ for copper metabolism, the liver is a primary site for copper homeostasis disruption and cuproptosis. Dysregulated copper metabolism and activated cuproptosis have been implicated in a spectrum of liver diseases, including Wilson's disease, metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and hepatocellular carcinoma (HCC). These findings provide profound insights into hepatic pathogenesis and reveal new therapeutic targets. This review summarizes the regulatory mechanisms of copper homeostasis, the related signaling pathways of cuproptosis, and the distinct mechanisms in various liver diseases. Furthermore, it highlights emerging therapeutic opportunities targeting copper ions to provide novel insights to explore and treat liver diseases.