| Autor: |
Joseph M. Hendricks, Cody Doubravsky, Eddie Wehri, Zhipeng Li, Melissa A. Roberts, Kirandeep Deol, Mike Lange, Irene Lasheras-Otero, S.J. Dixon, Kirill Bersuker, Julia Schaletzky, James A. Olzmann |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.12.14.520445 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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