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 (As4S4) 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.
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