Fig. 6

Schematic diagram of ferroptosis inducers enhanced cuproptosis induced by copper ionophores in primary liver cancer Ferroptosis inducers (FINs) sorafenib (Sora) and erastin (Era) promoted copper ionophores (CINs)-induced cuproptosis through stabilizing FDX1 protein and depleting intracellular GSH level. Mechanically, FINs stabilized FDX1 protein by suppressing mitochondrial proteases (AFG3L2 etc.) mediated FDX1 protein turnover. The stabilized FDX1 enhanced the protein lipoylation process and promoted the transfer of reduced copper ion, Cu¹⁺. In addition, FINs could also inhibit the import of cystine through suppressing the catalytic subunit (SLC7A11) of system Xc⁻, resulting in the decrease of GSH level, which could elevate the concentration of liable copper ion. Overall, these factors together augmented the aggregation of lipoylated proteins, and thus promoted cuproptosis in liver cancer cells. The diagram was created from BioRender.com