Fig. 2. The canonical pathway of p53 that regulates ferroptosis.

Iron metabolism: p53 promotes entry of Fe²⁺ into cells by regulating the lncRNA PVT1 to increase expression of TFR1, and promotes production of prototype iron by regulating SLC25A28 and FDXR, thus promoting ferroptosis. ROS metabolism: In the absence of amino acids, p53 promotes ROS production and lipid metabolism by promoting expression of GLS2. Lipid peroxidation: p53 increases the level of ALOX15 by promoting expression of SAT1, and then ALOX15 promotes lipid peroxidation to induce ferroptosis. P53 also inhibits DPP4-dependent lipid peroxidation to resist ferroptosis by transferring DPP4 to the nucleus. Elimination of lipid peroxides: p53 downregulates the level of CBS by inhibiting ELAVL1, or directly inhibits expression of CBS, thereby limiting GSH production. P53 also inhibits synthesis of GSH by inhibiting SLC7A11. Thus, p53 indirectly inhibits the activity of GPX4, reducing intracellular elimination of lipid peroxides and finally promoting ferroptosis. P53 also induces expression of p21, and then production of GSH increases, which increases GPX4 activity and the ability of cells to eliminate lipid peroxides. The green arrow indicates the stimulatory effect and the red arrow indicates the inhibitory effect.