Ferroptotic death is the penalty for losing control over three processes—iron metabolism, lipid peroxidation and thiol regulation—that are common in the pro-inflammatory environment where professional phagocytes fulfill their functions and yet survive. We hypothesized that redox reprogramming of 15-lipoxygenase (15-LOX) during the generation of pro-ferroptotic signal 15-hydroperoxy-eicosa-tetra-enoyl-phosphatidylethanolamine (15-HpETE-PE) modulates ferroptotic endurance. Here, we have discovered that inducible nitric oxide synthase (iNOS)/NO^•-enrichment of activated M1 (but not alternatively activated M2) macrophages/microglia modulates susceptibility to ferroptosis. Genetic or pharmacologic depletion/inactivation of iNOS confers sensitivity on M1 cells, whereas NO^• donors empower resistance of M2 cells to ferroptosis. In vivo, M1 phagocytes, in comparison to M2 phagocytes, exert higher resistance to pharmacologically induced ferroptosis. This resistance is diminished in iNOS-deficient cells in the pro-inflammatory conditions of brain trauma or the tumour microenvironment. The nitroxygenation of eicosatetraenoyl (ETE)-PE intermediates and oxidatively truncated species by NO^• donors and/or suppression of NO^• production by iNOS inhibitors represent a novel redox mechanism of regulation of ferroptosis in pro-inflammatory conditions.

Ferroptotic 死亡是失去对三个过程（铁代谢、脂质过氧化和硫醇调节）的控制的惩罚，这三个过程在促炎环境中很常见，在这个环境中，专业的吞噬细胞履行其功能并存活下来。我们假设在促铁死亡信号 15-hydroperoxy-eicosa-tetra-enyl-phosphatidylethanolamine (15-HpETE-PE) 的产生过程中 15-脂氧合酶 (15-LOX) 的氧化还原重编程调节铁死亡耐力。在这里，我们发现诱导型一氧化氮合酶 (iNOS)/NO ^•富集活化的 M1（但不是活化的 M2）巨噬细胞/小胶质细胞可调节对铁死亡的易感性。iNOS 的遗传或药理学消耗/失活赋予 M1 细胞敏感性，而 NO ^•捐赠者增强 M2 细胞对铁死亡的抵抗力。在体内，与 M2 吞噬细胞相比，M1 吞噬细胞对药理学诱导的铁死亡具有更高的抵抗力。在脑外伤或肿瘤微环境的促炎条件下，iNOS 缺陷细胞的这种抵抗力会减弱。^{NO •}供体对二十碳四烯酰 (ETE)-PE 中间体和氧化截短物质的氮氧化作用和/或 iNOS 抑制剂对 NO ^•产生的抑制代表了促炎条件下调节铁死亡的一种新型氧化还原机制。