Arsenic sulfide Triggers Ferroptosis in Hepatocellular Carcinoma Cells via TRPC6/GPX4 Signaling

Abstract Ferroptosis plays a vital role in the pathological process of numerous human diseases, including cancer. It is possible that ferroptosis stimulation could be used as a cancer treatment strategy. Due to this, ferroptosis-inducing drugs are gaining more attention for the clinical treatment of tumors. For the first time, we demonstrated that arsenic sulfide (As 4 S 4 ) initiated ferroptotic cell death in hepatocellular carcinoma (HCC) cells, which was concomitant with ROS accumulation, lipid peroxidation, and GSH depletion. Arsenic sulfide -mediated cell death in HCC cells was blocked by ferroptosis inhibitors ferrostatin-1 (Fer-1) and deferoxamine (DFO, an iron chelator), but not Z-VAD-FMK, necrosulfonamide, or chloroquine, suggesting that ferroptosis participated in arsenic sulfide -induced cell death. Transient receptor potential channel 6 (TRPC6) expression was notably inhibited under arsenic sulfide intervention and the overexpression of TRPC6 rescued the effects of arsenic sulfide on ferroptosis. Furthermore, glutathione peroxidase 4 (GPX4), was identified to interact with TRPC6 through confocal microscopy images and co-immunoprecipitation assay. In summary, arsenic sulfide exerts anticancer effects on HCC in vitro and in vivo by inducing ferroptosis via inhibiting TRPC6/GPX4 pathway. Our findings led us to conclude that arsenic sulfide could be considered as a prospective drug for liver cancer treatment.