Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis.

Ferroptosis is a regulated form of cell death associated with the iron-dependent accumulation of phospholipid hydroperoxides. 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. Through 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 defense pathways. [Display omitted] • Identification of structurally diverse small molecule inhibitors of FSP1 • FSEN1 is an uncompetitive FSP1 inhibitor that sensitizes cancer cells to ferroptosis • FSEN1 synergizes with GPX4 inhibitors and endoperoxide-based ferroptosis inducers Hendricks et al. identify a set of structurally diverse small molecules that inhibit FSP1, a CoQ oxidoreductase that suppresses ferroptosis. The most potent FSP1 inhibitor, ferroptosis sensitizer 1 (FSEN1) sensitizes cancer cells to ferroptosis and synergizes with several ferroptosis inducers, including GPX4 inhibitors and endoperoxide-containing molecules such as DHA. [ABSTRACT FROM AUTHOR]