p53 is an essential regulator of cell growth, metabolism, differentiation and death. TP53 (tumor protein p53) is famous for its function as a tumor suppressor. In recent years, a mass of research has provided evidence of its pivotal role in metabolic functions, cell apoptosis, growth arrest [
68‐
70], and indicates that p53 plays a bidirectional role in controlling ferroptosis.
p53 can promote ferroptosis to selectively deplete cancer cells via several approaches. Spermidine/spermine N1-acetyltransferase 1 (SAT1), a transcription target of p53, leads to lipid peroxidation and ferroptosis upon ROS stress. In this process, ALOX15 plays a critical role but not GPX4 or SLC7A11 [
71]. Through inhibiting the expression of SLC7A11, an acetylation-resistant TP53
3KR (K117R, K161R, K162R), can indirectly suppress the absorbency of cystine, which plays a key role in GSH biosynthesis. Moreover, depletion of GSH leads to lipid peroxidation, which then triggers ferroptosis [
72]. Furthermore, the loss of K98 acetylation on p53
4KR (K98R + K117R + K161R + K162R) compared to p53
3KR results in the loss in ability to induce ferroptosis, which indicates that acetylation is pivotal for p53-mediated ferroptosis [
73]. p53 targets gene
GLS2 (glutaminases2), relating to glutaminolysis, also involved in ferroptosis [
74]. SOCS1 (suppressor of cytokine signaling 1) can sensitize cells to ferroptosis by regulating the expression of some target genes of p53. SOCS1 exerts its function through regulating phosphorylation and stabilization of p53. Interestingly, SLC7A11 and SAT1 are both found as the SOCS1-dependent p53 targets, indicating that the SOCS1-p53 axis is involved in the ferroptosis pathway [
75]. On the other hand, p53 also suppresses ferroptosis in other cancer cells (e.g. Colorectal cancer). Loss of p53 prevents accumulation of dipeptidyl-peptidase-4 (DPP4) in the cell nucleus, and contributes to the formation of a complex of DPP4 and NOX1 (NADPH oxidase 1) on the plasma-membrane, thus enhancing lipid peroxidation, which results in ferroptosis. In contrast, by blocking DPP4 activity in a transcription-independent manner, the formation of DPP4-TP53 complex limits erastin-induced ferroptosis [
76]. In addition, stabilization of wild-type p53 postpones the onset of ferroptosis and CDKN1A (encoding p21CIP1/WAF1) is required in this process. This delay is also related to slower depletion of intracellular GSH and a reduced accumulation of toxic lipid-ROS [
77]. Several other molecules such as lncRNAs, and single-nucleotide polymorphisms can also help p53 play a dual role in ferroptosis [
78,
79]. For example, the Pro47Ser polymorphism (S47) can restrain erastin-induced GLS2 expression and ferroptosis [
78]. However, the exact mechanisms of the dual functions of p53 in ferroptosis have not been clearly uncovered. The effects of p53 and its epigenetic regulators in ferroptosis may contribute to a potential target in ferroptosis related diseases.