Disulfiram/copper exhibits anti-tumor activity against hepatocellular carcinoma via FTO/m6A/IGF2BP2/FDX1 signaling mediating cuproptosis

Drug repurposing is a promising strategy that can improve current cancer treatment. Disulfiram (DSF), which is used clinically for treating alcoholism, exhibits antitumor activity in various cancers, but the detailed molecular mechanisms remain incompletely understood. In this study, we demonstrated that diethyldithiocarbamate-copper complex (CuET), the main metabolite of DSF, exerts anti-tumor activity against hepatocellular carcinoma (HCC) by promoting cuproptosis. Mechanistically, CuET directly targets fat mass and obesity associated protein (FTO) and inhibits its activity, resulting in increased global N6-methyladenosine (m6A) mRNA modification that is recognized by insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2). Subsequently, CuET increases the stability of FDX1 transcript and upregulates FDX1, resulting in lipoylated protein aggregation and loss of Fe-S cluster proteins, and ultimately promotes cuproptosis in HCC cells. Our study showed that CuET induces cuproptosis in HCC cells by targeting the FTO/m6A/IGF2BP2/FDX1 signaling pathway, thereby exerting an anti-tumor effect, and highlights the promising potential of targeting FTO in cancer therapy.