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.