biostudies-literatureYang XNIAID NIH HHSNCI NIH HHSNINDS NIH HHS762-777.e9https://www.ebi.ac.uk/biostudies/studies/S-EPMC11209835biostudies-literatureUnknown36(4)Although the role of ferroptosis in killing tumor cells is well established, recent studies indicate that ferroptosis inducers also sabotage anti-tumor immunity by killing neutrophils and 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 pleckstrin homology-like domain family A member 2 (PHLDA2)-mediated ferroptosis pathway that is neither ACSL4-dependent nor requires common ferroptosis inducers. PHLDA2-mediated ferroptosis acts through the 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 common ferroptosis inducers; strikingly, losCell metabolismPHLDA2-mediated phosphatidic acid peroxidation triggers a distinct ferroptotic response during tumor suppression.PMC11209835R01 CA258390P30 CA008748R01 CA243142R37 NS061817R01 CA266342R01 CA166413R35 CA209896R01 CA258622P30 CA013696R01 CA204232R01 CA165065R01 CA254970U01 AI156923U01 AI156924R01 NS076511R01 NS061817R35 CA253059Stockwell BRGu WKon NChen DTycko BYang XBayir HKagan VEKapralov AALi ZZhang ZJiang XAmoscato AADuan STyurin VAWang ZSamovich SNDar HHfalsePHLDA2-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 anti-tumor immunity by killing neutrophils and 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 pleckstrin homology-like domain family A member 2 (PHLDA2)-mediated ferroptosis pathway that is neither ACSL4-dependent nor requires common ferroptosis inducers. PHLDA2-mediated ferroptosis acts through the 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 common ferroptosis inducers; strikingly, los2024-01-01T00:00:00Z2024 Apr2026-05-29T10:04:40.328Z2025-04-07T02:10:30.589ZS-EPMC112098353830926710.1016/j.cmet.2024.01.006