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 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. [Display omitted] • PHLDA2 promotes ferroptosis by interacting with ALOX12 in an ACSL4-independent manner • PHLDA2 promotes the oxidation of phosphatidic acid upon high levels of ROS • PHLDA2 inhibits tumor growth in immunodeficient and immunocompetent mouse models • PHLDA2-mediated ferroptosis occurs in vivo in absence of common ferroptosis inducers Yang et al. found that the phospholipid-binding protein, PHLDA2, triggers a distinct type of ferroptosis through phosphatidic acid peroxidation upon high levels of ROS. PHLDA2-mediated ferroptosis acts as a natural defense for tumor development by promoting ferroptosis in both immunodeficient and immunocompetent mouse models without any treatment from ferroptosis inducers. [ABSTRACT FROM AUTHOR]