Identification of a new small molecule that initiates ferroptosis in cancer cells by inhibiting the system Xc− to deplete GSH

Ferroptosis is a non-apoptotic cell death characterized by iron-mediated ROS accumulation and increasing lipid peroxidation. The activation of ferroptosis results in the destruction of cancer cells and overcoming the drug resistance associated with existing chemotherapeutic agents. It is essential to develop new ferroptosis inducers to provide new opportunities for cancer therapy. In this study, we found a small molecule Compound 8 which we had demonstrated to inhibit tumor growth in vivo initiated ferroptosis. Compound 8 treatment elevated the ferroptosis-related genes PTGS2 and CHAC1 mRNA levels in tumor cells. Ferroptosis inhibitors but not the necroptosis inhibitor or the apoptosis inhibitor can suppress the cell death induced by Compound 8. Compound 8 causes overall greater quantity of lipid peroxidation than the classic ferroptosis inducer Erastin through Flow cytometry analysis. The non-targeted lipidomic analysis also showed Compound 8 treatment resulted in oxidized lipid metabolites, similar to Erastin. The mechanism research showed that Compound 8 initiated ferroptosis by inhibiting the system Xc- to deplete GSH. Based on our previous study that Compound 8 blocked the interaction of PKM2 and VDAC3 (a regulator of ferroptosis) to inhibit tumor growth in vivo, Compound 8 may also trigger ferroptosis by regulating VADC3. Thus, Compound 8 not only will offer a potential tumor therapeutic alternative, but also provide an entrance to explore the new mechanism of ferroptosis.