==== Front
Cell Death Discov
Cell Death Discov
Cell Death Discovery
2058-7716
Nature Publishing Group UK London

37386007
1517
10.1038/s41420-023-01517-8
Review Article
Ferroptosis and the bidirectional regulatory factor p53
Xu Ren 1
Wang Wanning 2
http://orcid.org/0000-0002-9159-2747
Zhang Wenlong wenxu@jlu.edu.cn

3
1 Pulmonary and Critical Care Medicine Department, First Hospital of Jiliwn University, 130021 Changchun, China
2 grid.430605.4 0000 0004 1758 4110 Nephrology Department, First Hospital of Jilin University, 130021 Changchun, China
3 grid.415954.8 0000 0004 1771 3349 Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, 130033 Changchun, China
29 6 2023
29 6 2023
2023
9 19715 11 2022
16 6 2023
22 6 2023
© The Author(s) 2023
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Ferroptosis is a type of regulated cell death characterized by iron-mediated lipid peroxidation, in contrast with apoptosis, autophagy, and necrosis. It can be triggered by many pathological processes, including cellular metabolism, tumors, neurodegenerative diseases, cardiovascular diseases, and ischemia–reperfusion injuries. In recent years, ferroptosis has been discovered to be associated with p53. P53 is a tumor suppressor protein with multiple and powerful functions in cell cycle arrest, senescence, cell death, repair of DNA damage, and mitophagy. Emerging evidence shows that ferroptosis plays a crucial role in tumor suppression by p53. P53 functions as a key bidirectional regulator of ferroptosis by adjusting metabolism of iron, lipids, glutathione peroxidase 4, reactive oxygen species, and amino acids via a canonical pathway. In addition, a noncanonical pathway of p53 that regulates ferroptosis has been discovered in recent years. The specific details require to be further clarified. These mechanisms provide new ideas for clinical applications, and translational studies of ferroptosis have been performed to treat various diseases.

Subject terms

Cell death
Cancer
https://doi.org/10.13039/501100011789 Department of Science and Technology of Jilin Province (Jilin Province Science and Technology Department) 20210401174YY YDZJ202201ZYTS092 Zhang Wenlong issue-copyright-statement© Cell Death Differentiation Association (ADMC) 2023
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pmcFacts

P53 plays a crucial role in ferroptosis. It targets the key proteins and enzymes involved in ferroptosis such as SLC25A28, FDXR, SAT1-ALOX15, GLS2, SLC7A11, DPP4, p21, ALOX12, and iPLA2β. P53 also regulates noncoding RNAs to promote ferroptosis.

Regulation of ferroptosis by p53 is complex, bidirectional, and context dependent. P53 promotes ferroptosis to help the body eliminate tumor cells and abnormal cells. P53 can reduce the sensitivity of cells to ferroptosis and promote normal cell survival.

Translational research of p53 and ferroptosis demonstrates potential clinical prospects for tumors and ischemia–reperfusion injury.

Introduction

A form of iron-dependent cell death that cannot be hindered by genetic or chemical inhibitors of necroptosis or apoptosis was first reported a decade ago and named ferroptosis [1]. In subsequent research, researchers found that ferroptosis differs from apoptosis and necrosis in terms of genetics, biochemistry, and morphology [2]. It is characterized by lethal accumulation of iron and lipid hydroperoxides, and subsequent plasma membrane rupture and cell death [3]. There are a wide range of pathological conditions and human diseases associated with ferroptosis, including organ injury [4–6], organ fibrosis [7], tumors [8–12], neurodegenerative diseases [13], cardiovascular diseases [14], and gynecological diseases [15]. The complex mechanisms and cellular metabolic processes involved in ferroptosis are gradually being elucidated.

The tumor suppressor protein p53 was first discovered in the 1970s [16, 17]. P53 is at the center of a signaling network controlling cell proliferation and death, and is the guardian of genome integrity. The concentration of p53 protein in normal cells is very low, and p53 is activated when DNA damage, nutritional deficiency, hypoxia, or oxidative stress occur. P53 is a meaningful regulatory factor in ferroptosis that promotes or inhibits ferroptosis through canonical and noncanonical pathways. As a vital regulatory factor, p53 and its pathways provide potential targets for clinical treatment and novel interventions for many diseases.

Process of ferroptosis

Cells undergoing ferroptosis have unique morphological features, including lessened mitochondrial size, increased mitochondrial membrane density, reduced/absent mitochondrial cristae, ruptured mitochondrial outer membranes, and a normally sized nucleus but with no concentration of chromatin [2]. The process of ferroptosis involves iron, lipid, and reactive oxygen species (ROS) metabolism and antioxidant systems.

Abnormal metabolism and subsequent accumulation of iron

Iron is a material nutrient and has important biological functions, such as catalyzing various biochemical reactions by accepting and donating electrons [18]. Metabolic processing of iron includes its import, utilization, storage, and excretion from cells. Ferroptosis is triggered by an overload of intracellular iron, which is associated with abnormal iron metabolism (Fig. 1).Fig. 1 The process of ferroptosis and the involvement of iron, lipid, and GSH metabolism.

Intracellular excess Fe2+ enters the labile iron pool, causing the Fenton reaction, in which Fe2+ is oxidized to Fe3+, while the electron is transferred to H2O2 to form HO•. HO• initiates the oxidation of PUFAs of membrane PLs. The PUFA of a PL donates a hydrogen atom to HO•, leading to formation of a carbon-centered PL• that further reacts with intracellular molecular O2 to form a PL peroxyl radical (PLOO•). Next, from another PUFA moiety of a PL, PLOO• abstracts a hydrogen atom and is subsequently converted to PL hydroperoxide (PLOOH) accompanied by formation of a new PL•. PLOOH is cleaved in the presence of Fe2+ to form the PL alkoxyl radical (PLO•), which reacts with the PUFA of another PL to form PL alcohol (PLOH) and a new PL•, followed by another lipid radical chain reaction. There are three types of lipid oxidation enzymes: cyclooxygenase (COX), cytochrome P450 (CYP), and lipoxygenase (LOX). They initiate the enzymatic lipid peroxidation process. Lipid peroxides including PL free radicals can be eliminated by GPXs, MDA, or 4-HNE, but excess PL free radicals cause the unbounded peroxidation of PUFAs of membrane PLs, which eventually leads to destruction of the cell membrane. Intracellular Fe2+ and GPX4 are generated via iron and GSH metabolism, respectively. The red arrow represents the inhibitory effect, and the green arrow represents the promoting effect. 4-HNE 4-hydroxynonenal, DMT1 divalent metal transporter 1, DPP4 dipeptidyl peptidase-4, FPN ferroportin (also known as SLC40A1), GCL glutamate-cysteine ligase, GLS2 glutaminase 2, GPX4 glutathione peroxidase 4, GSH glutathione, GSS glutathione synthetase, HO• hydroxyl radical, LIP labile iron pool, LOX lipoxygenase, MDA malondialdehyde, MSRB2 methionine-R-sulfide reductase B2, NRF2 nuclear factor erythroid 2-related factor 2, p21 cyclin-dependent kinase inhibitor 1A, i.e., CDKN1A, PL phospholipid, PL• PL radical species, PLO• PL alkoxyl radical, PLOH PL alcohol, PLOO• PL peroxyl radical, PLOOH, PL hydroperoxide, PTGS2 (encodes cyclooxygenase-2, which is an enzyme that acts both as a peroxidase and a dioxygenase, and catalyzes lipid oxidation), PUFA polyunsaturated fatty acids, SCARA5 scavenger receptor class A member 5, SLC1A5 solute carrier family member 1 member A5, SLC7A11 solute carrier family 7 member A11, STEAP six transmembrane epithelial antigen of prostate, TFR1 transferrin receptor 1, ZIP8 Zrt- and Irt-like protein 8.

Cells import iron in four ways [18]. The most critical path is mediated by transferrin and transferrin receptor 1 (TFR1). Transferrin is a type of globulin that can chelate two Fe3+ ions and bind to TFR1. Then the Fe3+-transferrin-TFR1 complex is internalized via endocytosis and release Fe3+ which is reduced to Fe2+ [19]. Fe2+ subsequently enters the cytoplasm labile iron pool (LIP) via the action of divalent metal transporter 1 (DMT1). Furthermore, there are several types of ferri-reductases in serum, such as six transmembrane epithelial antigen of prostate (STEAP), ferric chelate reductase 1, and cytochrome B reductase 1, which can convert Fe3+ to Fe2+. In addition, Fe2+ enters cells through membrane transporters (such as ZIP8, ZIP14, and DMT1). Monocytes and macrophages can take up Fe2+ from porphyrin contained in hemoglobin [20]. In embryos and kidneys, ferritin enters cells through scavenger receptor class A member 5 [21].

Intracellular Fe2+ is transported into mitochondria to assist with cellular respiration and synthesis of Fe-S clusters and heme by mitoferrin 1 and 2 [22]. Some Fe2+ is stored in cells in the form of the LIP or ferritin. Fe2+ in the LIP is unstable, and can regulate cellular iron homeostasis and induce ferroptosis. The ferritin protein sequesters iron and is involved in iron transport and cell proliferation, immunosuppression, and angiogenesis [23]. Ferritin releases free iron through the action of nuclear receptor coactivator 4 (NCOA4) in a process named ferritinophagy [24]. NCOA4 is responsible for recruiting ferritin heavy chain polypeptides into autophagosomes so that lysosomes can degrade ferritin, resulting in an increase of free iron [25]. An increase in iron content triggers NCOA4 to interact with HERC2, an E3 ubiquitin ligase, which promotes ubiquitination and degradation of NCOA4. Knockdown of NCOA4 or autophagy-related gene (ATG) can inhibit ferritin degradation and ferroptosis induced by erastin, while NCOA4 overexpression promote ferroptosis.

Iron export relies on ferroportin-1 (FPN, also known as SLC40A1). FPN cooperates with ceruloplasmin or hephaestin, and transports Fe2+ out of cells [26]. It is the unique iron efflux pump, and its expression is dramatically suppressed in many types of tumors [27]. Compared to non-tumor cells, tumor cells have a high iron requirement and dependency, and therefore are more likely to undergo ferroptosis in response to ferroptosis-inducing drugs, and this is a promising novel way to kill therapy-resistant cancers [28].

Iron is utilized, stored, and exported in a balanced manner. Iron accumulation caused by abnormal metabolism is the basis of ferroptosis. Various iron chelators such as ferrostatin-1 [29] and liproxstatin-1 can inhibit ferroptosis. The process after accumulation of iron includes lipid oxidation and inactivation of antioxidant systems.

Intracellular accumulation of iron-induced ROS

When too much Fe2+ enters the cell, the utilization or exportation of Fe2+ is reduced and the intracellular Fe2+ level increases. Excess Fe2+ initiates the Fenton reaction. The process of the Fenton reaction is as follows: Fe2+ is oxidized to Fe3+, while the electron is transferred to hydrogen peroxide (H2O2) to form the hydroxyl radical (HO•), which is the most chemically active ROS [30]. In addition to HO•, another two ROS molecules, superoxide (O2•-) and H2O2, are involved in iron redox reactions. ROS function as driver of ferroptosis by triggering lipid peroxidation, and they can mediate autophagy to induce ferroptosis by degrading ferritin and increasing TFR1 expression upon exposure to erastin [31].

Lipid metabolism and peroxidation

Lipid peroxidation induced by iron accumulation plays a central role in ferroptosis. Phospholipids (PLs), which are divided into sphingomyelin and glycerophospholipids, are the basic components of cellular membranes. The major fatty acids in sphingomyelin are saturated fatty acids or monounsaturated fatty acids, which cannot induce ferroptosis. Glycerophospholipids contain a saturated fatty acid at C-1, an unsaturated fatty acid (PUFA) [arachidonic acid (AA)] at C-2, and a phosphatidic ester group at C-3 of the glycerol backbone. Peroxidation of PUFAs at C-2 can drive ferroptosis. De novo synthesized fatty acids must be incorporated into PLs by acyl-CoA synthetases (ACSs). Phosphatidylethanolamines containing AA or adrenic acid (AdA) are key PLs that can be oxidized and drive ferroptosis. ACS long-chain family member 4 (ACSL4) first converts AA to acylated AA, and lysophosphatidylcholine acyltransferase 3 catalyzes the incorporation of acylated AA into the PL.

A study [32] confirmed that the expression of ACSL4 in a cell subgroup of triple negative breast cancer is related to its sensitivity to ferroptosis inducers. A similar correlation was observed in drug-resistant mesenchymal carcinoma cells and renal carcinoma cells. Inhibition of ACSL4 expression may be the main mechanism underlying desensitization of cells to ferroptosis. On the contrary, elevation of the expression or activity of ACSL4 may promote ferroptosis under various pathophysiological conditions, such as ischemia–reperfusion injury, and in response to radiation.

ROS (mainly HO•) produced by the Fenton reaction initiate the nonenzymatic free radical chain oxidative reaction of PUFAs on cell membranes and thereby change these membranes to instigate ferroptosis [33]. The oxidized PUFAs on cellular membranes can disturb the assembly of these membranes; change the properties of lipid bilayers in terms of disrupted ion gradients, decreased fluidity, slower lateral diffusion, and increased permeability; influence lipid-lipid and lipid-protein interaction dynamics; destroy the physicochemical properties of membranes; influence the transport of nutrients; affect membrane-initiated signaling pathways; and impact metabolic processes, eventually leading to cell death [33].

Lipid peroxidation can be divided into spontaneous oxidation and enzymatic oxidation. Spontaneous oxidation of lipids is a chain reaction driven by free radicals (Fig. 1). The hydrogen of a PUFA is obtained by the hydroxyl group to form a carbon-centered lipid radical (L•). The rapid reaction of oxygen molecules with L• produces lipid peroxide groups (LOO•). Subsequently, LOO• obtains hydrogen from a nearby PUFA to form hydroperoxide (LOOH) and a new L•, and LOOH is converted to an alkoxy group (LO•) with the cooperation of Fe2+. These new L• and LO• groups react with an adjacent PUFA to cause another chain reaction. This spontaneous process is catalyzed by iron and oxygen. In addition, some lipoxygenases (LOX) can directly oxidize PUFAs and PUFA-containing lipids in biofilms, suggesting that LOX mediate ferroptosis [34]. In the process of enzyme-catalyzed lipid peroxidation, a PUFA is introduced into membrane PLs and neutral lipids, and produces large amounts of lipid peroxidation products, 4-hydroxynonaenoic acid (4-HNE), malondialdehyde, PL LOOH (PLOOH), and various oxidized and modified proteins. Knockout of arachidonate 15-lipoxygenase (ALOX15) or application of the LOX inhibitor baicalein can protect mice from ischemic injury.

Ferroptosis suppressor protein 1 (FSP1) is a ferroptosis resistance factor that was identified in recent years [35]. It can prevent PL peroxidation, especially in the presence of both α-tocopherol and CoQ10. In the presence of FSP1, CoQ10 is reduced to CoQ10-H2 by NADPH to inhibit the propagation of PL peroxidation.

Impairment of the system Xc--GSH-GPX4 axis promotes ferroptosis

To diminish oxidative damage, cells have many antioxidant systems. As the main detoxifying factor for lipid peroxides, glutathione peroxidase 4 (GPX4) converts active PLOOH to inactive PLOH, and thus inhibits lipid peroxidation. This is also an important regulatory target of the canonical ferroptosis pathway (Fig. 1) [36]. GPX4 is a selenocysteine-containing glutathione peroxidase. It can inhibit the hydrogen peroxide reaction of PLs and cholesterol, even when they are embedded in membranes and lipoproteins. GPX4 overexpression prevents ferroptosis induced by RSL3, while knockdown or inhibition of GPX4 promotes it [37].

GSH is a cofactor of the lipid peroxide reductase GPX4. The level of intracellular GSH is regulated by the cystine-glutamate antiporter (system Xc-) [38]. SLC7A11 is a crucial component of system Xc-, which is located on the cell surface and is responsible for the exchange of extracellular cystine and intracellular glutamate. Once cystine enters the cell, its disulfide bond breaks to form cysteine, which is one of three substrates for GSH synthesis. Thus, inhibition of SLC7A11 reduces the import of cystine and subsequently reduces synthesis of GSH, which greatly decreases the level of GSH in cells, and this is followed by lower elimination of lipid peroxides via GPX4 [2].

Beclin 1 is a key regulator of macroautophagy/autophagy. It can promote ferroptosis through inhibition of system Xc- [39]. Beclin 1 is phosphorylated by the AMP-activated protein kinase (AMPK) to initiate complex formation with SLC7A11 [39]. In beclin 1-overexpressing cells, the level of the beclin 1-SLC7A11 complex is increased, GSH depletion is serious, and the lipid oxidative stress reaction is aggravated, which promotes ferroptosis. On the contrary, after deletion of the gene encoding beclin 1, formation of the beclin 1-SLC7A11 complex is blocked, the level of the antioxidant GSH is increased, and cells are resistant to ferroptosis. Both vivo and vitro experiments found that the Tal-beclin 1 activating peptide can promote ferroptosis induced by erastin [40].

P53 and ferroptosis

In recent years, a growing number of studies have confirmed that p53 is closely associated with metabolic pathways of ferroptosis and is a critical regulatory factor of ferroptosis [8]. Regulation of ferroptosis by p53 is complex, context-dependent, and tissue-specific, and can promote the occurrence of ferroptosis and also prevent it. When lipid peroxidation damage is mild and can be repaired, p53 helps cells to restrain ferroptosis. However, if the damage persists or is too severe, p53 will induce ferroptosis and damaged cells will be removed. Regulation of ferroptosis by p53 can be divided into the canonical and noncanonical pathways according to whether it depends on GPX4.

The canonical pathway of p53 that regulates ferroptosis

The canonical pathway of p53 that regulates ferroptosis involves metabolism of iron, lipids, amino acids, and ROS (Fig. 2). The core factor is GPX4.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.

P53 and iron metabolism

P53 regulates ferroptosis by affecting iron metabolism and ferredoxin reductase (FDXR) levels [41]. There are two targets of p53 in mitochondria: solute carrier family 25 member 28 (SLC25A28) and FDXR. In hepatic stellate cells, p53 enhances the activity of SLC25A28, and thereby causes abnormal assembly of redox-active iron and augments ferroptosis [42]. FDXR is an enzyme in mitochondria that can transfer electrons from NADPH to cytochrome P450. Under the action of RSL3 or erastin, p53 induces transcriptional expression of FDXR to promote ferroptosis [41]. The exact effect and mechanism remain to be clarified. The p53-FDXR loop maintains mitochondrial iron homeostasis and is critical for tumor suppression. This adaptive regulatory mechanism requires further study.

P53 and ALOX15

P53 can regulate the p53-spermidine/spermine N1-acetyltransferase 1 (SAT1)-ALOX15 metabolic pathway to promote ferroptosis [43]. SAT1 is a rate-limiting enzyme that regulates conversion of spermidine and spermine to putrescine during polyamine catabolism. SAT1 is also a direct target of p53. Under oxidative stress, upon treatment with the DNA-damaging agent doxorubicin, or induction by Nutlin-3 (a small molecule MDM2 inhibitor), p53 targets SAT1 and promotes its expression. This increases the level of ALOX15, which oxygenates PUFAs to promote ferroptosis without affecting SLC7A11 or GPX4 [43].

P53 and glutamine metabolism

Glutamine metabolism is another pathway involved in the regulation of ferroptosis. Glutaminase-2 (GLS2) is a mitochondrial enzyme that catalyzes the first step of glutamine catabolism to glutamate. GLS2 is also a direct transcriptional target of p53 to positively regulate ferroptosis. In the absence of amino acids or even entire or partial depletion of cystine, glutamine can induce ferroptosis in a serum-dependent manner [44]. P53 binds to the response element in the GLS2 and induces its transcription. Thereafter, GLS2 converts glutamine into glutamate and then into α-ketoglutarate, and the low level of GSH inhibits GPX4, which promotes ferroptosis [45]. Jennis et al. found a p53 variant (called S47) in African-descent populations that has impaired GLS2 transactivation ability [46]. Tumor cells with S47 have a decreased level of GLS2 and are resistant to ferroptosis. Mice with S47 are susceptible to spontaneous cancers. These findings indicate that ferroptosis is crucial for the mechanism underlying p53 tumor inhibition by targeting GLS2.

P53 and system Xc-/GPX4

As mentioned earlier, GPX4 is a selenocysteine-containing glutathione peroxidase that reduces lipid peroxides to the corresponding alcohols [47]. Regulation of GPX4 by p53 is bidirectional. P53 inhibits GPX4 by inhibiting the SLC7A11-GSH pathway or cystathionine-β-synthase (CBS), and then promotes ferroptosis. It also promotes production of GPX4 through the p21/GSH pathway to prevent ferroptosis.

Jiang et al. first reported that p53 transcriptionally inhibits SLC7A11 to sensitize cells to ferroptosis [8]. They identified that p53 directly targets the responsive element in the promoter of SLC7A11 to inhibit its expression, and then a cascade reaction occurs. As uptake of extracellular cystine declines, GSH synthesis falls, GPX4 activity decreases, the level of lipid peroxides increases, and finally ferroptosis occurs. P53 also inhibits the serine trans-sulfuration pathway by repressing CBS. This limits GSH production and thereby indirectly inhibits the enzymatic activity of GPX4, eventually promoting ferroptosis [48, 49].

p53 can also promote ferroptosis induced by RSL3 or erastin through upregulation of PTGS2. PTGS2 encodes cyclooxygenase-2, which is an enzyme that acts both as a peroxidase and a dioxygenase, and catalyzes lipid oxidation. A study by Yang et al. revealed that PTGS2 is the most upregulated gene during erastin- or RSL3-induced ferroptosis [50].

P53 and noncoding RNAs

P53 also can induce ferroptosis by regulating noncoding RNAs. It regulates expression of numerous noncoding RNAs, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) [51–53]. Meanwhile, p53 is also reciprocally regulated by various noncoding RNAs. The embryonic lethal vision-like protein 1 (ELAVL1)-LINC00336-miR-6852-CBS and PVT1-miR-214-TFR1 axes are well studied. ELAVL1 is an ELAV-like RNA-binding protein that binds to and stabilizes the lncRNA LINC00336 in lung cancer cells [49]. This stabilizes the miRNA miR-6852 and increases expression of CBS, making cells insensitive to ferroptosis. P53 promotes ferroptosis by binding to the promoter region of ELAVL1 and inhibiting its expression. This is followed by destabilization of LINC00336 and release of miR-6852. As the level of CBS decreases, ferroptosis is promoted.

In another axis, the lncRNA PVT1 promotes ferroptosis by restraining the miR-214-mediated downregulation of TFR1. P53 can induce expression of PVT1 to promote ferroptosis in cancer and acute ischemic stroke-induced tissue injuries [54, 55].

P53 and dipeptidyl peptidase-4 (DPP4)

DPP4 is a ubiquitous enzyme located on the cell membrane or in a soluble form. It activates lipid peroxidation by interacting with NADPH oxidase 1 (NOX1), leading to ferroptosis [56]. In human colorectal carcinoma, p53 forms a complex with DPP4 and translocates it to the nucleus, and thus inhibits plasma membrane-associated DPP4-dependent lipid peroxidation to restrain ferroptosis [56].

The noncanonical pathway of p53 that regulates ferroptosis

In the noncanonical pathway, p53 regulates ferroptosis through the arachidonate 12-lipoxygenase (ALOX12), arachidonate lipoxygenase 3 (ALOXE3), or iPLA2β pathway. These are also potential hot research topics.

P53 and ALOX12/ALOXE3

ALOX12 and ALOXE3 belong to the lipoxygenase family, and are involved in the noncanonical pathway of p53-mediated ferroptosis regulation that is independent of GSH and GPX4. Under normal conditions, SLC7A11 binds to and sequesters ALOX12 from its substrate, PUFAs, including those esterified in membranes [57]. In response to redox stress, p53 enhances the activity of ALOX12 by downregulating SLC7A11 (Fig. 3). As ALOX12 is released, oxidized membrane PUFAs produce lipid peroxides and initiate ferroptosis [58].Fig. 3 The noncanonical pathway of p53 that regulates ferroptosis.

Following redox stress, p53 enhances the activities of ALOX12 and ALOXE3 by downregulating SLC7A11. Then, ALOX12 and ALOXE3 are separately released and subsequently oxidize membrane PUFAs, to produce lipid peroxides and initiate ferroptosis. When lipid peroxidation damage is low and can be repaired, p53 targets IPLA2β, which eliminates acyl tails from lipids and releases oxidized fatty acids. The latter are further detoxified by antioxidants in the cytoplasm, and thus ferroptosis is inhibited. When the damage persists or is too severe, p53 induces ferroptosis and thereby eliminates damaged cells. The green arrow indicates the stimulatory effect and the red arrow indicates the inhibitory effect.

ALOXE3 was reported to induce ferroptosis similar to ALOX12 in glioblastoma (GBM) cells [59]. Under normal conditions, SLC7A11 also sequesters ALOXE3 from its substrate, 12-hydroperoxyeicosatetraenoic acids (a catalytic product of ALOX12). In response to stress, p53 inhibits SLC7A11, resulting in release of ALOXE3 and decreased production and secretion of 12-hydroperoxyeicosatetraenoic acids, followed by induction of ferroptosis. Notably, the p53/SLC7A11/ALOX12 and p53/SLC7A11/ALOXE3 axes independently and cooperatively regulate ferroptosis and participate in tumor suppression, both of which are independent of GSH and GPX4. Hence, the two axes may be a novel way to induce ferroptosis beside the classic ferroptosis model.

P53 and iPLA2β

In addition, there is a novel antiferroptosis mechanism that is independent of GPX4 and FSP1. After cleaving the peroxidized PUFAs of membrane PLs, free radicals are released and cleared by various cellular antioxidant systems to solve the problem of PL peroxidation [60]. The core executor of this mechanism is iPLA2β (also called phospholipase A2 group VI, PLA2G6), a calcium-independent phospholipase. IPLA2β is also a target of p53, and can eliminate acyl tails from lipids and release oxidized fatty acids, which are further detoxified by antioxidants in the cytoplasm, leading to negative regulation of ferroptosis [60, 61]. The p53-GPX4 axis eliminates lipid peroxides and stabilizes the internal environment, while the p53-iPLA2β axis solves the abnormal radical disturbance. However, the reactions are complex and context dependent. When lipid peroxidation damage is low and can be repaired, p53 transactivates iPLA2β to restrain ferroptosis. However, if the damage persists or is too severe, ferroptosis induced by p53 will occur with the removal of damaged cells [57]. In particular, p53 and iPLA2β are tightly associated with tumors and neurodegenerative diseases, especially Parkinson’s disease. The p53-iPLA2β axis and other antiferroptosis pathways work together to protect against cell death due to iron overload and ensure the proper physiological benefits of ferroptosis.

P53 bidirectionally regulates ferroptosis

P53 positively or negatively regulates ferroptosis in different cell types and in response to different stress factors through several independent signaling pathways. As mentioned earlier, p53 promotes ferroptosis mainly by promoting activity of SLC25A28 and expression of FDXR, inhibiting transcription of SLC7A11, promoting expression of GLS2, and increasing the levels of SAT1-ALOX15. This promotion of ferroptosis helps the body to eliminate tumor cells and abnormal cells.

P53 can reduce the sensitivity of cells to ferroptosis and promote normal cell survival, especially when the injury or stress is mild. Positive or negative regulation of ferroptosis by p53 also depends on the cell type. Xie et al. found that p53 wild-type colorectal cancer (CRC) cells were insensitive to erastin, but the sensitivity of these cells to erastin was restored upon inhibition of p53 activity by gene knockout or drugs [56]. Further mechanistic research found that p53 has differential effects on SLC7A11 expression in CRC and non-CRC cells. Inhibition of p53 increased SLC7A11 mRNA and protein expression in U2OS and MCF7 cells. By contrast, inhibition of p53 reduced SLC7A11 expression in human CRC cells. This research revealed that p53 can promote transport of DPP4 into the nucleus and thus reduce the impact of DPP4 on NOX1, thereby reducing the levels of lipid ROS and ferroptosis.

P21 (also known as cyclin-dependent kinase inhibitor 1 A, CDKN1A) is also a target of p53. It mediates the function of p53 by inducing cell cycle arrest and senescence in response to stress signals [62, 63]. Meanwhile, p21 can be induced by p53 to increase production of GSH, which further promotes the function of GPX4, leading to increased elimination of toxic lipids and ROS to inhibit ferroptosis [64].

Translational research

Translational research of ferroptosis regulation by p53 mainly focuses on tumors and ischemia–reperfusion injury. Preclinical studies have shown that upregulation of ferroptosis can induce tumor regression, while downregulation of ferroptosis reduces ischemia–reperfusion injury of heart, brain, and lung tissues. Thus, there are potential clinical applications to target p53 and ferroptosis.

Regulation of ferroptosis by p53 not only plays an important role in tumor suppression but also enhances sensitivity of tumor cells to radiotherapy, and even has predictive value for antitumor efficacy and prognosis. D13, a novel compound isolated and extracted from the natural saponin Albiziabioside A, triggers apoptosis and ferroptosis of human colon cancer HCT116 cells by activating p53 through the mitochondrial pathway [65, 66]. It has strong inhibitory activity against multidrug-resistant cancer cells. Interestingly, this compound exhibits highly selective inhibition of tumors without eliciting toxic effects on normal organs in vivo. Other ferroptosis inducers have yielded promising data in research of nonsmall cell lung cancer, ovarian cancer, castration-resistant prostate cancer, triple negative breast cancer, colon cancer and NK/T cell lymphoma [67–72]. Interfering with tumor metabolism to induce ferroptosis is a novel antitumor treatment strategy. In addition, treatment with a combination of ferroptosis inducers and radiotherapy has yielded satisfactory results. Induction of ferroptosis by radiotherapy is related to activation of p53 and often suggests a better prognosis. However, expression of SLC7A11 induced by radiotherapy plays a key role in tumor progression and radio-resistance, especially in tumors with p53 mutations or deficiency. Notably, ferroptosis inducers can overcome tumor escape mediated by SLC7A11 and restore the sensitivity of p53 mutant tumors to radiotherapy [73]. In the future, treatment with a combination of molecular targeted drugs, chemotherapy, and immune checkpoint inhibitors together with ferroptosis inducers may yield more promising data. In addition, ferroptosis has prognostic value for certain cancers. A prognostic model including prognosis-related differentially expressed ferroptosis-related genes in head and neck squamous cell carcinoma was built to guide precise and individualized treatment [74]. The prognostic score of this model is closely related to p53 mutation, treatment with six cytotoxic drugs, and expression of immune checkpoint inhibitor-related genes. This ferroptosis-related gene model can not only predict the therapeutic effect in patients with head and neck tumors but also determine the prognosis of these patients. Translational studies of ferroptosis regulation by p53 will lead to increasingly accurate models for tumor treatment, efficacy prediction, and prognosis judgment.

Studies of ferroptosis regulation by p53 have also yielded promising results in alleviating ischemia–reperfusion injury. Acute lung injury is a life-threatening disease with high mortality. Interestingly, animal studies have shown that ferroptosis is involved in acute lung injury triggered by ischemia–reperfusion injury [75]. Inhibition of p53 transcriptional activity can protect normal lung tissue from acute injury induced by ischemia–reperfusion injury via the nuclear factor-like 2 signaling pathway. This provides a potential therapeutic option for acute lung injury caused by ischemia–reperfusion. Acute myocardial infarction (AMI) accounts for a considerable proportion of fatalities. Myocardial reperfusion by thrombolysis or using a stent is the basic therapeutic strategy for AMI. However, ischemia–reperfusion injury cannot be ignored. Recent studies in animal models have shown that overexpression of USP22, SIRT1, and SLC7A11 can inhibit p53 transcriptional activity and thereby ferroptosis, reducing infarct size and improving cardiac function [76]. This provides a new strategy to overcome ischemia–reperfusion injury after AMI treatment. A common site of ischemia–reperfusion injury is the central nervous system. Cerebral ischemia is a common cause of death of hippocampal neurons, stroke, and fatality. Modulation of ferroptosis by SLC7A11 and p53 affects the role of hippocampal neurons [77]. Alteration of the ferritin level can reduce ferroptosis mediated by p53 and SLC7A11. This may be a novel mechanism underlying the possible neuroprotective effect of ferritin on free radical injury and has potential clinical value. In another study, increasing expression of SLC7A11 and GPX4 and inhibiting activation of p53 could reduce early brain injury associated with ferroptosis [78]. Inhibiting ferroptosis by suppressing p53 may be a novel therapeutic strategy for early brain injury. Thus, blocking ferroptosis regulated by p53 activation may become a new strategy for treatment of ischemic diseases.

Conclusion

Regulation of ferroptosis by p53 is very complex and delicate. Different cell types, different stress factors, and even different intensities of the same stress factor may trigger different p53 signaling pathways and lead to different cell fates. Control of ferroptosis by p53 through canonical and noncanonical pathways is context-dependent. Many details of the mechanisms still need to be clarified. Further translational research will help to elucidate these mechanisms and master regulation of ferroptosis by p53 to tackle tumors and other diseases.

Author contributions

RX wrote the manuscript. WZ and WW were responsible for revision of the manuscript.

Funding

This work was supported by grants from the Science and Technology Development Project of Jilin Province (20210401174YY and YDZJ202201ZYTS092 to WZ).

Competing interests

The authors declare no competing interests.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References

1. Yang WS Kim KJ Gaschler MM Patel M Shchepinov MS Stockwell BR Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis Proc Natl Acad Sci USA 2016 113 E4966 75 10.1073/pnas.1603244113 27506793
2. Dixon SJ Lemberg KM Lamprecht MR Skouta R Zaitsev EM Gleason CE Ferroptosis: an iron-dependent form of nonapoptotic cell death Cell. 2012 149 1060 72 10.1016/j.cell.2012.03.042 22632970
3. Hou W Xie Y Song X Sun X Lotze MT Zeh HJ 3rd Autophagy promotes ferroptosis by degradation of ferritin Autophagy. 2016 12 1425 8 10.1080/15548627.2016.1187366 27245739
4. Li N Wang W Zhou H Wu Q Duan M Liu C Ferritinophagy-mediated ferroptosis is involved in sepsis-induced cardiac injury Free Radic Biol Med 2020 160 303 18 10.1016/j.freeradbiomed.2020.08.009 32846217
5. Ding C Ding X Zheng J Wang B Li Y Xiang H miR-182-5p and miR-378a-3p regulate ferroptosis in I/R-induced renal injury Cell Death Dis 2020 11 929 10.1038/s41419-020-03135-z 33116120
6. Jacobs W Lammens M Kerckhofs A Voets E Van San E Van Fatal lymphocytic cardiac damage in coronavirus disease 2019 (COVID-19): autopsy reveals a ferroptosis signature ESC Heart Fail 2020 7 3772 81 10.1002/ehf2.12958 32959998
7. Vetuschi A Cappariello A Onori P Gaudio E Latella G Pompili S Ferroptosis resistance cooperates with cellular senescence in the overt stage of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis Eur J Histochem 2022 66 3 10.4081/ejh.2022.3391
8. Jiang L Kon N Li T Wang SJ Su T Hibshoosh H Ferroptosis as a p53-mediated activity during tumour suppression Nature. 2015 520 57 62 10.1038/nature14344 25799988
9. Li J Liu J Xu Y Wu R Chen X Song X Tumor heterogeneity in autophagy-dependent ferroptosis Autophagy. 2021 17 3361 74 10.1080/15548627.2021.1872241 33404288
10. Lee JY Nam M Son HY Hyun K Jang SY Kim JW Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer Proc Natl Acad Sci USA 2020 117 32433 42 10.1073/pnas.2006828117 33288688
11. Yang J Zhou Y Xie S Wang J Li Z Chen L Metformin induces ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer J Exp Clin cancer Res 2021 40 206 10.1186/s13046-021-02012-7 34162423
12. Weijiao Y Fuchun L Mengjie C Xiaoqing Q Hao L Yuan L Immune infiltration and a ferroptosis-associated gene signature for predicting the prognosis of patients with endometrial cancer Aging. 2021 13 16713 32 10.18632/aging.203190 34170849
13. Ashraf A Jeandriens J Parkes HG So PW Iron dyshomeostasis, lipid peroxidation and perturbed expression of cystine/glutamate antiporter in Alzheimer’s disease: evidence of ferroptosis Redox Biol 2020 32 101494 10.1016/j.redox.2020.101494 32199332
14. Wu X Qin K Iroegbu CD Xiang K Peng J Guo J Genetic analysis of potential biomarkers and therapeutic targets in ferroptosis from coronary artery disease J Cell Mol Med 2022 26 2177 90 10.1111/jcmm.17239 35152560
15. Liao T Xu X Ye X Yan J DJ-1 upregulates the Nrf2/GPX4 signal pathway to inhibit trophoblast ferroptosis in the pathogenesis of preeclampsia Sci Rep 2022 12 2934 10.1038/s41598-022-07065-y 35190654
16. Linzer DI Levine AJ Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells Cell. 1979 17 43 52 10.1016/0092-8674(79)90293-9 222475
17. Lane DP Crawford LV T antigen is bound to a host protein in SV40-transformed cells Nature. 1979 278 261 3 10.1038/278261a0 218111
18. Camarena V Huff TC Wang G Epigenomic regulation by labile iron Free Radic Biol Med 2021 170 44 9 10.1016/j.freeradbiomed.2021.01.026 33493555
19. Kleven MD Dlakić M Lawrence CM Characterization of a single b-type heme, FAD, and metal binding sites in the transmembrane domain of six-transmembrane epithelial antigen of the prostate (STEAP) family proteins J Biol Chem 2015 290 22558 69 10.1074/jbc.M115.664565 26205815
20. Kristiansen M Graversen JH Jacobsen C Sonne O Hoffman HJ Law SK Identification of the haemoglobin scavenger receptor Nature. 2001 409 198 201 10.1038/35051594 11196644
21. Li JY Paragas N Ned RM Qiu A Viltard M Leete T Scara5 is a ferritin receptor mediating non-transferrin iron delivery Dev Cell 2009 16 35 46 10.1016/j.devcel.2008.12.002 19154717
22. Shaw GC Cope JJ Li L Corson K Hersey C Ackermann GE Mitoferrin is essential for erythroid iron assimilation Nature. 2006 440 96 100 10.1038/nature04512 16511496
23. Buranrat B Connor JR Cytoprotective effects of ferritin on doxorubicin-induced breast cancer cell death Oncol Rep 2015 34 2790 6 10.3892/or.2015.4250 26352101
24. Mancias JD Wang X Gygi SP Harper JW Kimmelman AC Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy Nature. 2014 509 105 9 10.1038/nature13148 24695223
25. Quiles Del Rey M Mancias JD NCOA4-mediated ferritinophagy: a potential link to neurodegeneration Front Neurosci 2019 13 238 10.3389/fnins.2019.00238 30930742
26. Potdar AA Sarkar J Das NK Ghosh P Gratzl M Fox PL Computational modeling and analysis of iron release from macrophages PLoS Comput Biol 2014 10 e1003701 10.1371/journal.pcbi.1003701 24991925
27. Shang Y Luo M Yao F Wang S Yuan Z Yang Y Ceruloplasmin suppresses ferroptosis by regulating iron homeostasis in hepatocellular carcinoma cells Cell Signal 2020 72 109633 10.1016/j.cellsig.2020.109633 32283255
28. Hassannia B Vandenabeele P Vanden Berghe T Targeting ferroptosis to iron out cancer Cancer Cell 2019 35 830 49 10.1016/j.ccell.2019.04.002 31105042
29. Skouta R Dixon SJ Wang J Dunn DE Orman M Shimada K Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models J Am Chem Soc 2014 136 4551 6 10.1021/ja411006a 24592866
30. Liu X Chen C Han D Zhou W Cui Y Tang X SLC7A11/GPX4 inactivation-mediated ferroptosis contributes to the pathogenesis of triptolide-induced cardiotoxicity Oxid Med Cell Longev 2022 2022 3192607 35757509
31. Park E Chung SW ROS-mediated autophagy increases intracellular iron levels and ferroptosis by ferritin and transferrin receptor regulation Cell Death Dis 2019 10 822 10.1038/s41419-019-2064-5 31659150
32. Doll S Proneth B Tyurina YY Panzilius E Kobayashi S Ingold I ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition Nat Chem Biol 2017 13 91 8 10.1038/nchembio.2239 27842070
33. Catalá A Díaz M Editorial: Impact of lipid peroxidation on the physiology and pathophysiology of cell membranes Front Physiol 2016 7 423 10.3389/fphys.2016.00423 27713704
34. Mikulska-Ruminska K Anthonymuthu TS Levkina A Shrivastava IH Kapralov AA Bayir H NO(●) represses the oxygenation of arachidonoyl PE by 15LOX/PEBP1: mechanism and role in ferroptosis Int J Mol Sci 2021 22 10 10.3390/ijms22105253
35. Doll S Freitas FP Shah R Aldrovandi M da Silva MC Ingold I FSP1 is a glutathione-independent ferroptosis suppressor Nature. 2019 575 693 8 10.1038/s41586-019-1707-0 31634899
36. Wu J Minikes AM Gao M Bian H Li Y Stockwell BR Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling Nature. 2019 572 402 6 10.1038/s41586-019-1426-6 31341276
37. Jhelum P Santos-Nogueira E Teo W Haumont A Lenoel I Stys PK Ferroptosis mediates cuprizone-induced loss of oligodendrocytes and demyelination J Neurosci 2020 40 9327 41 10.1523/JNEUROSCI.1749-20.2020 33106352
38. Stockwell BR Friedmann Angeli JP Bayir H Bush AI Conrad M Dixon SJ Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease Cell. 2017 171 273 85 10.1016/j.cell.2017.09.021 28985560
39. Kang R Zhu S Zeh HJ Klionsky DJ Tang D BECN1 is a new driver of ferroptosis Autophagy. 2018 14 2173 5 10.1080/15548627.2018.1513758 30145930
40. Song X Zhu S Chen P Hou W Wen Q Liu J AMPK-mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system X(c)(-) activity Curr Biol 2018 28 2388 99.e5 10.1016/j.cub.2018.05.094 30057310
41. Zhang Y Qian Y Zhang J Yan W Jung YS Chen M Ferredoxin reductase is critical for p53-dependent tumor suppression via iron regulatory protein 2 Genes Dev 2017 31 1243 56 10.1101/gad.299388.117 28747430
42. Zhang Z Guo M Shen M Kong D Zhang F Shao J The BRD7-P53-SLC25A28 axis regulates ferroptosis in hepatic stellate cells Redox Biol 2020 36 101619 10.1016/j.redox.2020.101619 32863216
43. Ou Y Wang SJ Li D Chu B Gu W Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses Proc Natl Acad Sci USA 2016 113 E6806 12 10.1073/pnas.1607152113 27698118
44. Gao M Monian P Quadri N Ramasamy R Jiang X Glutaminolysis and transferrin regulate ferroptosis Mol Cell 2015 59 298 308 10.1016/j.molcel.2015.06.011 26166707
45. Hu W Zhang C Wu R Sun Y Levine A Feng Z Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function Proc Natl Acad Sci USA 2010 107 7455 60 10.1073/pnas.1001006107 20378837
46. Jennis M Kung CP Basu S Budina-Kolomets A Leu JI Khaku S An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model Genes Dev 2016 30 918 30 10.1101/gad.275891.115 27034505
47. Seiler A Schneider M Förster H Roth S Wirth EK Culmsee C Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death Cell Metab 2008 8 237 48 10.1016/j.cmet.2008.07.005 18762024
48. Ou Y Wang SJ Jiang L Zheng B Gu W p53 Protein-mediated regulation of phosphoglycerate dehydrogenase (PHGDH) is crucial for the apoptotic response upon serine starvation J Biol Chem 2015 290 457 66 10.1074/jbc.M114.616359 25404730
49. Wang M Mao C Ouyang L Liu Y Lai W Liu N Long noncoding RNA LINC00336 inhibits ferroptosis in lung cancer by functioning as a competing endogenous RNA Cell Death Differ 2019 26 2329 43 10.1038/s41418-019-0304-y 30787392
50. Yang WS SriRamaratnam R Welsch ME Shimada K Skouta R Viswanathan VS Regulation of ferroptotic cancer cell death by GPX4 Cell. 2014 156 317 31 10.1016/j.cell.2013.12.010 24439385
51. Dangelmaier E Lazar SB Lal A Long noncoding RNAs: p53’s secret weapon in the fight against cancer? PLoS Biol 2019 17 e3000143 10.1371/journal.pbio.3000143 30759134
52. Zhang Y Luo M Cui X O’Connell D Yang Y Long noncoding RNA NEAT1 promotes ferroptosis by modulating the miR-362-3p/MIOX axis as a ceRNA Cell Death Differ 2022 29 1850 63 10.1038/s41418-022-00970-9 35338333
53. Fu H Zhang Z Li D Lv Q Chen S Zhang Z LncRNA PELATON, a ferroptosis suppressor and prognositic signature for GBM Front Oncol 2022 12 817737 10.3389/fonc.2022.817737 35574340
54. Lu J Xu F Lu H LncRNA PVT1 regulates ferroptosis through miR-214-mediated TFR1 and p53 Life Sci 2020 260 118305 10.1016/j.lfs.2020.118305 32827544
55. Olivero CE Martínez-Terroba E Zimmer J Liao C Tesfaye E Hooshdaran N p53 activates the long noncoding RNA Pvt1b to inhibit Myc and suppress tumorigenesis Mol Cell 2020 77 761 74.e8 10.1016/j.molcel.2019.12.014 31973890
56. Xie Y Zhu S Song X Sun X Fan Y Liu J The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity Cell Rep 2017 20 1692 704 10.1016/j.celrep.2017.07.055 28813679
57. Liu Y Gu W p53 in ferroptosis regulation: the new weapon for the old guardian Cell Death Differ 2022 29 895 910 10.1038/s41418-022-00943-y 35087226
58. Chu B Kon N Chen D Li T Liu T Jiang L ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway Nat Cell Biol 2019 21 579 91 10.1038/s41556-019-0305-6 30962574
59. Yang X Liu J Wang C Cheng KK Xu H Li Q miR-18a promotes glioblastoma development by down-regulating ALOXE3-mediated ferroptotic and anti-migration activities Oncogenesis 2021 10 15 10.1038/s41389-021-00304-3 33579899
60. Chen D Chu B Yang X Liu Z Jin Y Kon N iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4 Nat Commun 2021 12 3644 10.1038/s41467-021-23902-6 34131139
61. Malley KR Koroleva O Miller I Sanishvili R Jenkins CM Gross RW The structure of iPLA(2)β reveals dimeric active sites and suggests mechanisms of regulation and localization Nat Commun 2018 9 765 10.1038/s41467-018-03193-0 29472584
62. Tarangelo A Rodencal J Kim JT Magtanong L Long JZ Dixon SJ Nucleotide biosynthesis links glutathione metabolism to ferroptosis sensitivity Life Sci Alliance 2022 5 4 10.26508/lsa.202101157
63. Tarangelo A Magtanong L Bieging-Rolett KT Li Y Ye J Attardi LD p53 Suppresses metabolic stress-induced ferroptosis in cancer cells Cell Rep 2018 22 569 75 10.1016/j.celrep.2017.12.077 29346757
64. Tarangelo A Dixon S The p53-p21 pathway inhibits ferroptosis during metabolic stress Oncotarget. 2018 9 24572 3 10.18632/oncotarget.25362 29872487
65. Wei G Sun J Hou Z Luan W Wang S Cui S Novel antitumor compound optimized from natural saponin Albiziabioside A induced caspase-dependent apoptosis and ferroptosis as a p53 activator through the mitochondrial pathway Eur J Med Chem 2018 157 759 72 10.1016/j.ejmech.2018.08.036 30142612
66. Chen V Bo C Gu W The roads to ferroptosis under homeostatic versus pathological conditions Mol Cell Oncol 2021 8 1970477 10.1080/23723556.2021.1970477 34859139
67. Meng M, Huang M, Liu C, Wang J, Ren W, Cui S, et al. Local anesthetic levobupivacaine induces ferroptosis and inhibits progression by up-regulating p53 in non-small cell lung cancer. Aging. 2021. 10.18632/aging.203138.
68. Zhang Y Xia M Zhou Z Hu X Wang J Zhang M p53 Promoted ferroptosis in ovarian cancer cells treated with human serum incubated-superparamagnetic iron oxides Int J Nanomed 2021 16 283 96 10.2147/IJN.S282489
69. Zhou X Zou L Chen W Yang T Luo J Wu K Flubendazole, FDA-approved anthelmintic, elicits valid antitumor effects by targeting P53 and promoting ferroptosis in castration-resistant prostate cancer Pharmacol Res 2021 164 105305 10.1016/j.phrs.2020.105305 33197601
70. Ye S Xu M Zhu T Chen J Shi S Jiang H Cytoglobin promotes sensitivity to ferroptosis by regulating p53-YAP1 axis in colon cancer cells J Cell Mol Med 2021 25 3300 11 10.1111/jcmm.16400 33611811
71. Wei Y Zhu Z Hu H Guan J Yang B Zhao H Eupaformosanin induces apoptosis and ferroptosis through ubiquitination of mutant p53 in triple-negative breast cancer Eur J Pharmacol 2022 924 174970 10.1016/j.ejphar.2022.174970 35469839
72. He C Wang C Liu H Shan B Kayadiol exerted anticancer effects through p53-mediated ferroptosis in NKTCL cells BMC Cancer 2022 22 724 10.1186/s12885-022-09825-5 35778693
73. Lei G Zhang Y Hong T Zhang X Liu X Mao C Ferroptosis as a mechanism to mediate p53 function in tumor radiosensitivity Oncogene. 2021 40 3533 47 10.1038/s41388-021-01790-w 33927351
74. Fan X Ou Y Liu H Zhan L Zhu X Cheng M A ferroptosis-related prognostic signature based on antitumor immunity and tumor protein p53 mutation exploration for guiding treatment in patients with head and neck squamous cell carcinoma Front Genet 2021 12 732211 10.3389/fgene.2021.732211 34616431
75. Li Y Cao Y Xiao J Shang J Tan Q Ping F Inhibitor of apoptosis-stimulating protein of p53 inhibits ferroptosis and alleviates intestinal ischemia/reperfusion-induced acute lung injury Cell Death Differ 2020 27 2635 50 10.1038/s41418-020-0528-x 32203170
76. Ma S Sun L Wu W Wu J Sun Z Ren J USP22 protects against myocardial ischemia-reperfusion injury via the SIRT1-p53/SLC7A11-dependent inhibition of ferroptosis-induced cardiomyocyte death Front Physiol 2020 11 551318 10.3389/fphys.2020.551318 33192549
77. Chen W Jiang L Hu Y Tang N Liang N Li XF Ferritin reduction is essential for cerebral ischemia-induced hippocampal neuronal death through p53/SLC7A11-mediated ferroptosis Brain Res 2021 1752 147216 10.1016/j.brainres.2020.147216 33333054
78. Kuang H Wang T Liu L Tang C Li T Liu M Treatment of early brain injury after subarachnoid hemorrhage in the rat model by inhibiting p53-induced ferroptosis Neurosci Lett 2021 762 136134 10.1016/j.neulet.2021.136134 34311053