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

Cell Metab. 2024 Jan 29:S1550-4131(24)00005-6. doi: 10.1016/j.cmet.2024.01.006. Online ahead of print.ABSTRACTAlthough 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, 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 PA 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.PMID:38309267 | DOI:10.1016/j.cmet.2024.01.006

Source: Cell Metabolism - February 3, 2024 Category: Cytology Authors: 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 H ülya Bayir Brent R Stockwell Valerian E Kagan Wei Gu Source Type: research