Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA, USA.
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
Nat Chem Biol. 2020 Mar;16(3):302-309. doi: 10.1038/s41589-020-0472-6. Epub 2020 Feb 17.
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.
铁死亡广泛涉及包括肾脏、肝脏和大脑在内的各种组织中的退行性疾病，是多种原发性和治疗抵抗性癌症中可靶向的脆弱性。细胞膜中磷脂氢过氧化物的积累是铁死亡的标志和限速步骤；然而，导致脂质过氧化的酶仍未得到很好的描述。使用全基因组、CRISPR-Cas9 介导的抑制筛选，我们发现细胞色素 P450 氧化还原酶 (POR) 是在表现出内在和诱导性铁死亡易感性的癌细胞中发生铁死亡细胞死亡所必需的。通过在癌细胞中遗传耗尽 POR，我们揭示 POR 在广泛的谱系和细胞状态下以及对不同的铁死亡诱导机制的反应中都有助于铁死亡。通过系统脂质组学分析，我们进一步将 POR 的活性映射到铁死亡中的脂质过氧化步骤。因此，我们的工作表明 POR 是铁死亡的关键介质，也是开发抗铁死亡治疗药物的潜在可用药靶。
