Ferroptosis—an iron-dependent, non-apoptotic cell death process—is involved in various degenerative diseases and represents a targetable susceptibility in certain cancers 1 . The ferroptosis-susceptible cell state can either pre-exist in cells that arise from certain lineages or be acquired during cell-state transitions 2 – 5 . However, precisely how susceptibility to ferroptosis is dynamically regulated remains poorly understood. Here we use genome-wide CRISPR–Cas9 suppressor screens to identify the oxidative organelles peroxisomes as critical contributors to ferroptosis sensitivity in human renal and ovarian carcinoma cells. Using lipidomic profiling we show that peroxisomes contribute to ferroptosis by synthesizing polyunsaturated ether phospholipids (PUFA-ePLs), which act as substrates for lipid peroxidation that, in turn, results in the induction of ferroptosis. Carcinoma cells that are initially sensitive to ferroptosis can switch to a ferroptosis-resistant state in vivo in mice, which is associated with extensive downregulation of PUFA-ePLs. We further find that the pro-ferroptotic role of PUFA-ePLs can be extended beyond neoplastic cells to other cell types, including neurons and cardiomyocytes. Together, our work reveals roles for the peroxisome–ether-phospholipid axis in driving susceptibility to and evasion from ferroptosis, highlights PUFA-ePL as a distinct functional lipid class that is dynamically regulated during cell-state transitions, and suggests multiple regulatory nodes for therapeutic interventions in diseases that involve ferroptosis. The cellular organelles peroxisomes contribute to the sensitivity of cells to ferroptosis by synthesizing polyunsaturated ether phospholipids, and changes in the abundances of these lipids are associated with altered sensitivity to ferroptosis during cell-state transitions.

中文翻译：

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醚脂质的可塑性促进铁死亡的易感性和逃避

铁死亡 - 一种依赖于铁的非凋亡细胞死亡过程 - 涉及各种退行性疾病，并代表某些癌症 1 的可靶向易感性。铁死亡易感细胞状态可以预先存在于来自某些谱系的细胞中，也可以在细胞状态转换 2 – 5 期间获得。然而，对铁死亡的易感性究竟是如何动态调节的仍知之甚少。在这里，我们使用全基因组 CRISPR-Cas9 抑制筛选来确定氧化细胞器过氧化物酶体作为人类肾和卵巢癌细胞铁死亡敏感性的关键因素。使用脂质组学分析，我们表明过氧化物酶体通过合成多不饱和醚磷脂（PUFA-ePLs）促进铁死亡，多不饱和醚磷脂作为脂质过氧化的底物，反过来，导致铁死亡的诱导。最初对铁死亡敏感的癌细胞可以在小鼠体内转变为铁死亡抵抗状态，这与 PUFA-ePL 的广泛下调有关。我们进一步发现 PUFA-ePLs 的促铁凋亡作用可以从肿瘤细胞扩展到其他细胞类型，包括神经元和心肌细胞。总之，我们的工作揭示了过氧化物酶体 - 醚 - 磷脂轴在驱动易感性和逃避铁死亡中的作用，突出显示 PUFA-ePL 作为一种独特的功能性脂质类，在细胞状态转变期间动态调节，并建议多个调节节点用于治疗干预涉及铁死亡的疾病。