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Nat Chem Biol DOI:10.1038/s41589-020-0472-6

Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis.

Publication TypeJournal Article
Year of Publication2020
AuthorsZou, Y, Li, H, Graham, ET, Deik, AA, Eaton, JK, Wang, W, Sandoval-Gomez, G, Clish, CB, Doench, JG, Schreiber, SL
JournalNat Chem Biol
Volume16
Issue3
Pages302-309
Date Published2020 Mar
ISSN1552-4469
Abstract

Ferroptosis is widely involved in degenerative diseases in various tissues including kidney, liver and brain, and is a targetable vulnerability in multiple primary and therapy-resistant cancers. Accumulation of phospholipid hydroperoxides in cellular membranes is the hallmark and rate-limiting step of ferroptosis; however, the enzymes contributing to lipid peroxidation remain poorly characterized. Using genome-wide, CRISPR-Cas9-mediated suppressor screens, we identify cytochrome P450 oxidoreductase (POR) as necessary for ferroptotic cell death in cancer cells exhibiting inherent and induced susceptibility to ferroptosis. By genetic depletion of POR in cancer cells, we reveal that POR contributes to ferroptosis across a wide range of lineages and cell states, and in response to distinct mechanisms of ferroptosis induction. Using systematic lipidomic profiling, we further map POR's activity to the lipid peroxidation step in ferroptosis. Hence, our work suggests that POR is a key mediator of ferroptosis and potential druggable target for developing antiferroptosis therapeutics.

DOI10.1038/s41589-020-0472-6
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/32080622?dopt=Abstract

Alternate JournalNat. Chem. Biol.
PubMed ID32080622
Grant ListU01CA217848 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) /
R35GM127045 / / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) /