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

Joseph M Hendricks; Cody E Doubravsky; Eddie Wehri; Zhipeng Li; Melissa A Roberts; Kirandeep K Deol; Mike Lange; Irene Lasheras-Otero; Jeremiah D Momper; Scott J Dixon; Kirill Bersuker; Julia Schaletzky; James A Olzmann

doi:10.1016/j.chembiol.2023.04.007

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

Cell Chem Biol. 2023 Sep 21;30(9):1090-1103.e7. doi: 10.1016/j.chembiol.2023.04.007. Epub 2023 May 12.

Affiliations

¹ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
² The Henry Wheeler Center for Emerging and Neglected Diseases, University of California, Berkeley, Berkeley, CA 94720, USA.
³ Cancer Signaling Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), 31008 Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain.
⁴ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
⁵ Department of Biology, Stanford University, Stanford, CA 94305, USA.
⁶ The Henry Wheeler Center for Emerging and Neglected Diseases, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: jschaletzky@berkeley.edu.
⁷ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Miller Institute for Basic Research in Science, University of California, Berkeley, Berkeley, CA 94720, USA; Chan Zuckerberg Biohub - San Francisco, San Francisco, CA 94158, USA. Electronic address: olzmann@berkeley.edu.

Abstract

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.

Keywords: FSP1; GPX4; cancer; cell death; coenzyme Q10; endoperoxide; ferroptosis; glutathione; lipid peroxidation; small molecule screen.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antioxidants / metabolism
Cell Death
Ferroptosis*
Humans
Lipid Peroxidation
Neoplasms* / drug therapy

Substances

Antioxidants

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

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding