Harnessing copper-iron crosstalk: A novel strategy to combat hepatocellular carcinoma.

Copper and iron trigger distinct cuproptosis and ferroptosis as homeostasis is disrupted which would drive hepatocellular carcinoma (HCC) progression. Mitochondrial copper overload impairs protein lipoylation and iron-sulfur cluster stability which induces proteotoxic stress through accumulation of lipoylated TCA cycle enzymes. Elevated copper metabolism paradoxically increases their susceptibility to cuproptosis in HCC cells. Ferroptosis is characterized by iron-dependent lipid peroxidation resulting from insufficient antioxidant protection, particularly impairment of the GSH-GPX4 system that normally reduces lipid hydroperoxides. NRF2 and FSP1 serve as key regulators of HCC sensitivity by modulating antioxidant capacity and lipid metabolism. Dual targeting of these pathways offers a promising therapeutic strategy against HCC. Yet direct clinical evidence demonstrating therapeutic benefit from pharmacological induction of cuproptosis or coordinated cuproptosis-ferroptosis targeting in HCC is currently lacking. We explore the differential impacts of cuproptosis and ferroptosis on tumor progression and discuss the potential therapeutic implications of co-regulating these two cell death mechanisms in HCC.