PHLDA2-mediated phosphatidic acid peroxidation triggers a distinct ferroptotic response during tumor suppression

Although the role of ferroptosis in killing tumor cells is well established, recent studies indicate that ferroptosis inducers also sabotage the anti-tumor immunity by killing neutrophils thus unexpectedly, stimulate tumor growth, raising a serious issue about whether ferroptosis effectively suppresses tumor development in vivo. Through genome-wide CRISPR-Cas9 screenings, we discover a PHLDA2-mediated ferroptosis pathway that is neither ACSL4-dependent nor requires common ferroptosis inducers. PHLDA2-mediated ferroptosis acts through peroxidation of phosphatidic acid (PA) upon high levels of ROS. ROS-induced ferroptosis is critical for tumor growth in the absence of common ferroptosis inducers; strikingly, loss of PHLDA2 abrogates ROS-induced ferroptosis and promotes tumor growth but has no obvious effect in normal tissues in both immunodeficient and immunocompetent mouse tumor models. These data demonstrate that PHLDA2-mediated phosphatidic acid peroxidation triggers a distinct ferroptosis response critical for tumor suppression and reveal, that PHLDA2-mediated ferroptosis occurs naturally in vivo without any treatment from ferroptosis inducers.尽管铁死亡（ferroptosis）杀伤肿瘤细胞的作用已得到广泛证实，但近期研究表明，铁死亡诱导剂还可通过杀伤中性粒细胞破坏抗肿瘤免疫，反而意外地促进肿瘤生长，这引发了一个关键科学问题：铁死亡在体内能否有效抑制肿瘤发生。本研究通过全基因组CRISPR-Cas9筛选，发现一条由PHLDA2介导的铁死亡通路，该通路既不依赖ACSL4，也无需常见的铁死亡诱导剂。PHLDA2介导的铁死亡可在活性氧（reactive oxygen species, ROS）高水平存在时，通过催化磷脂酸（phosphatidic acid, PA）的过氧化反应发挥作用。在缺乏常见铁死亡诱导剂的情况下，活性氧诱导的铁死亡对肿瘤生长至关重要；值得注意的是，PHLDA2缺失可阻断活性氧诱导的铁死亡并促进肿瘤生长，但在免疫缺陷及免疫健全小鼠的肿瘤模型中，对正常组织均无明显影响。上述研究结果表明，PHLDA2介导的磷脂酸过氧化可触发一种独特的铁死亡应答，该应答对肿瘤抑制具有关键作用；同时本研究还揭示，PHLDA2介导的铁死亡可在体内自然发生，无需任何铁死亡诱导剂处理。