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.

铁死亡广泛参与各种组织的退行性疾病，包括肾脏、肝脏和大脑，并且是多种原发性和耐药性癌症的可靶向脆弱性。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的特征仍然很差。使用全基因组 CRISPR-Cas9 介导的抑制筛选，我们确定细胞色素 P450 氧化还原酶 (POR) 是癌细胞中铁死亡细胞死亡所必需的，这些癌细胞表现出固有的和诱导的对铁死亡的易感性。通过在癌细胞中 POR 的遗传耗竭，我们揭示了 POR 有助于在广泛的谱系和细胞状态中发生铁死亡，并响应不同的铁死亡诱导机制。使用系统的脂质组学分析，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，也是开发抗铁死亡疗法的潜在药物靶点。