Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis
By Y. Zou, Haoxin Li, E. T. Graham, A. Deik, J. Eaton, Wenyu Wang, G. Sandoval-Gomez, C. Clish, John G Doench, Stefan Schreiber. Nature Chemical Biology, 2020
642 citations recorded by the source corpus.
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. Using genome-wide CRISPR–Cas9-mediated suppressor screens, cytochrome P450 oxidoreductase was identified as a contributor to ferroptotic cell death by promoting phospholipid peroxidation in various cellular lineages.
Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/65cb664c95b26e83f1831838ef85592244ef72ee
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Citations in the corpus
- CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4 (2022, background): “Cellular lipid composition and fatty acid metabolism control ferroptosis (Dixon and Stockwell, 2019; Kraft et al., 2020; Zou et al., 2020).”
- Emerging mechanisms and disease relevance of ferroptosis (2020, background): “It remains possible that other irondependent enzymes contribute to lipid peroxidation in some circumstances; recently, cytochrome P450 oxidoreductase was implicated as a driver of lipid peroxidation during ferroptosis [22].”
- Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “73,80 These studies suggested that several iron-dependent enzymes can promote lipid peroxidation and ferroptosis.”
- Ferroptosis in infection, inflammation, and immunity (2021, background): “In addition to free PUFAs, i.e., the polyunsaturated ether phospholipids (PUFA-ePLs) synthesized in peroxisome (Zou et al., 2020a), lysosomal degradation of lipid droplets by lipophagy (Bai et al., 2019) or glutamine-derived anaplerotic flux that provides α-ketoglutarate to the tricarboxylic acid…”
- Ferroptosis in cancer therapy: a novel approach to reversing drug resistance (2022, background): “The pro-ferroptotic role of POR has also been demonstrated by genetic depletion across a wide range of lineages and cell states [31].”