小柯机器人

美国哥伦比亚大学Wei Gu小组发现，PHLDA2介导的磷脂酸过氧化反应在肿瘤抑制过程中引发了独特的铁死亡反应。相关论文于2024年2月2日在线发表于国际学术期刊《细胞—代谢》。

通过全基因组CRISPR-Cas9筛选，研究人员发现了一种PHLDA2（pleckstrin homology-likedomain family A member 2）介导的铁死亡途径，它既不依赖于ACSL4，也不需要常见的铁死亡诱导剂。PHLDA2介导的铁死亡反应是在高水平活性氧（ROS）作用下通过磷脂酸（PA）的过氧化作用进行的。

在没有常见的铁卟啉诱导剂的情况下，ROS诱导的铁死亡对肿瘤的生长至关重要；令人震惊的是，在免疫缺陷和免疫功能正常的小鼠肿瘤模型中，缺失PHLDA2会减弱ROS诱导的铁死亡并促进肿瘤生长，但对正常组织没有明显影响。这些数据证明了PHLDA2介导的PA过氧化反应触发了一种对抑制肿瘤至关重要的独特的铁死亡反应，并揭示了PHLDA2介导的铁死亡反应在体内自然发生，而无需任何铁死亡诱导剂的处理。

研究人员表示，尽管铁死亡在杀死肿瘤细胞方面的作用已得到公认，但最近的研究表明，铁死亡诱导剂也会通过杀死中性粒细胞来破坏抗肿瘤免疫，从而意外地刺激肿瘤生长，这就提出了一个严峻的问题，即铁死亡是否能有效抑制体内肿瘤的发展。

附：英文原文

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

Author: Xin Yang, Zhe Wang, Svetlana N. Samovich, Alexander A. Kapralov, Andrew A. Amoscato, Vladimir A. Tyurin, Haider H. Dar, Zhiming Li, Shoufu Duan, Ning Kon, Delin Chen, Benjamin Tycko, Zhiguo Zhang, Xuejun Jiang, Hülya Bayir, Brent R. Stockwell, Valerian E. Kagan, Wei Gu

Issue&Volume: 2024-02-02

Abstract: Although the role of ferroptosis in killing tumor cells is well established, recentstudies indicate that ferroptosis inducers also sabotage anti-tumor immunity by killingneutrophils and thus unexpectedly stimulate tumor growth, raising a serious issueabout whether ferroptosis effectively suppresses tumor development in vivo. Through genome-wide CRISPR-Cas9 screenings, we discover a pleckstrin homology-likedomain family A member 2 (PHLDA2)-mediated ferroptosis pathway that is neither ACSL4-dependentnor requires common ferroptosis inducers. PHLDA2-mediated ferroptosis acts throughthe peroxidation of phosphatidic acid (PA) upon high levels of reactive oxygen species(ROS). ROS-induced ferroptosis is critical for tumor growth in the absence of commonferroptosis inducers; strikingly, loss of PHLDA2 abrogates ROS-induced ferroptosisand promotes tumor growth but has no obvious effect in normal tissues in both immunodeficientand immunocompetent mouse tumor models. These data demonstrate that PHLDA2-mediatedPA peroxidation triggers a distinct ferroptosis response critical for tumor suppressionand reveal that PHLDA2-mediated ferroptosis occurs naturally in vivo without any treatment from ferroptosis inducers.

DOI: 10.1016/j.cmet.2024.01.006

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(24)00005-6

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