p53 in ferroptosis regulation: the new weapon for the old guardian.

Although the conventional activities of p53 such as cell cycle arrest, senescence, and apoptosis are well accepted as the major checkpoints in stress responses, accumulating evidence implicates the importance of other tumor suppression mechanisms. Among these unconventional activities, an iron-dependent form of non-apoptotic cell death, termed ferroptosis, attracts great interest. Unlike apoptotic cell death, activation of p53 alone is not sufficient to induce ferroptosis directly; instead, through its metabolic targets, p53 is able to modulate the ferroptosis response in the presence of ferroptosis inducers such as GPX4 inhibitors or high levels of ROS. Here, we review the role of ferroptosis in p53-mediated tumor suppression, with a focus on what cellular factors are critical for p53-dependent ferroptosis during tumor suppression and how p53 modulates both the canonical (GPX4-dependent) and the non-canonical (GPX4-independent) ferroptosis pathways. We also discuss the possibility of targeting p53-mediated ferroptotic responses for the treatment of human cancers and potentially, other diseases.