ABSTRACT
Ferroptosis is a regulated form of cell death associated with the iron-dependent accumulation of lipid peroxides. Inducing ferroptosis is a promising approach to treat therapy resistant cancer. Ferroptosis suppressor protein 1 (FSP1) promotes ferroptosis resistance in cancer by generating the antioxidant form of coenzyme Q10 (CoQ). Despite the important role of FSP1, few molecular tools exist that target the CoQ-FSP1 pathway. Exploiting a series of chemical screens, we identify several structurally diverse FSP1 inhibitors. The most potent of these compounds, ferroptosis sensitizer 1 (FSEN1), is an uncompetitive inhibitor that acts selectively through on target inhibition of FSP1 to sensitize cancer cells to ferroptosis. Furthermore, a synthetic lethality screen reveals that FSEN1 synergizes with endoperoxide-containing ferroptosis inducers, including dihydroartemisinin, to trigger ferroptosis. These results provide new tools that catalyze the exploration of FSP1 as a therapeutic target and highlight the value of combinatorial therapeutic regimes targeting FSP1 and additional ferroptosis inducers.
Competing Interest Statement
J.A.O. is a member of the scientific advisory board for Vicinitas Therapeutics. S.J.D. is a member of the scientific advisory board for Ferro Therapeutics and Hillstream BioPharma, Inc. J.S. is a member of the board of directors for Zenith Therapeutics and a scientific advisor to Lyterian Biosciences and Organos. S.J.D., J.A.O., J.M.H., E.W., J.S., C.D., and K.B. have ferroptosis-related patent applications.