Disulfiram-induced c-FOS influences lipid metabolism and angiogenesis in hepatocellular carcinoma

Lipid metabolism disorders and increased angiogenesis play key roles in the tumorigenesis of hepatocellular carcinoma (HCC). Intracellular metal ion disorders such as cuproptosis and ferroptosis have been progressively identified. However, whether copper ions have other effects outside the already recognized mechanisms of cell death is just as worthy of investigation. In particular, the effects on lipid metabolism and angiogenesis have important roles in the development of HCC. Our study revealed that disulfiram (DSF), a copper ion carrier, not only had a significant antitumor effect in vitro and in vivo, but also significantly inhibited angiogenesis and reversed abnormal lipid metabolism. Through transcriptome analysis, m1A methylation analysis, and functional validation, we identified c-FOS as a key target in DSF-induced methylation changes. In summary, DSF can reduce the modifications of c-FOS caused by the m1A methyltransferase TRMT10C, then regulate downstream genes MCAM and PCSK9, ultimately affecting angiogenesis and lipid metabolism. Moreover, high levels of expression of TRMT10C and PCSK9 in human HCC tumor tissues were associated with poor prognosis, while c-FOS showed the opposite pattern, confirming that the TRMT10C-c-FOS-PCSK9 axis is an important mechanism in HCC. In conclusion, copper ion carrier-DSF promotes the expression of c-FOS by inhibiting the m1A methyltransferase TRMT10C, thereby reversing the dysregulation of lipid metabolism and inhibiting angiogenesis in HCC.