p53 is a central transcriptional regulatory protein in the tumor-suppressor network. Its functions extend beyond DNA damage responses, cell-cycle arrest, and apoptosis to amino acid metabolism, redox homeostasis, and lipid oxidation. Ferroptosis is a form of regulated cell death driven by uncontrolled iron-dependent membrane phospholipid peroxidation. The intersection between p53 and ferroptosis mainly occurs at the SLC7A11–GSH–GPX4 antioxidant defense system, polyamine and lipid oxidation, and cellular stress adaptation. Among these mechanisms, the p53–SLC7A11 axis represents the central framework for understanding the pro-ferroptotic function of p53, whereas p21- and DPP4-related regulation reflects its pronounced context dependence.

Keywords: p53; TP53; ferroptosis; SLC7A11; GPX4; SAT1; p21; DPP4

1 Molecular Functions and Tumor-Suppressive Roles of p53

1.1 TP53 Gene and p53 Protein

TP53 is a classical tumor-suppressor gene, and its encoded p53 protein belongs to the stress-responsive transcription factor family. Under normal conditions, p53 is generally maintained at a low level. DNA damage, replication stress, aberrant oncogene activation, oxidative stress, and metabolic imbalance can promote p53 stabilization and activation, allowing it to regulate the cell cycle, damage repair, metabolic adaptation, senescence, and cell death through different target genes. p53 therefore constitutes an important regulatory node connecting cellular stress signals with cell-fate decisions.

1.2 MDM2–p53 Negative Feedback Regulation

MDM2 is an important negative regulator of p53 that can bind p53 and promote its ubiquitination and protein degradation. MDM2 itself is also a transcriptional target of p53, thereby forming an MDM2–p53 negative feedback loop. Under stress conditions, p53 stabilization enhances its transcriptional regulatory activity, while disruption of the MDM2–p53 interaction can also increase p53 levels in cells with functional TP53. The MDM2–p53 axis therefore represents an important pharmacological entry point connecting p53 functional regulation with ferroptosis research.

1.3 Major Tumor-Suppressive Functions of p53

(1) Cell-Cycle Arrest and DNA Damage Response

p53 can induce the expression of target genes such as CDKN1A/p21 and restrict Cyclin–CDK-mediated cell-cycle progression, allowing damaged cells to temporarily stop proliferation and gain time for DNA repair. When damage persists or cannot be repaired, p53 can further promote entry into senescence or cell-death programs.

(2) Regulation of Apoptosis

Under severe cellular stress, p53 can regulate pro-apoptotic molecules such as BAX, PUMA, and NOXA, promoting changes in mitochondrial outer-membrane permeability and initiating apoptosis. This mechanism represents an important component of the classical tumor-suppressive function of p53 but does not encompass all of its antitumor activities.

(3) Metabolic and Redox Regulation

p53 can alter glucose metabolism, amino acid utilization, mitochondrial function, glutathione homeostasis, and lipid oxidation. Because ferroptosis is highly dependent on cysteine availability, GSH–GPX4 defense, and the abundance of oxidizable membrane lipids, the metabolic regulatory capacity of p53 constitutes the major molecular basis for its involvement in ferroptosis.

2 Molecular Basis and Core Characteristics of Ferroptosis

2.1 Basic Characteristics of Ferroptosis

Ferroptosis is a form of regulated cell death characterized by the sustained accumulation of iron-dependent membrane phospholipid peroxidation. Its molecular basis differs from caspase-dependent apoptosis, and its key event is not a nonspecific increase in total ROS. Instead, phospholipids containing polyunsaturated fatty acids undergo sustained oxidation while the cellular capacity to eliminate phospholipid peroxides becomes insufficient, ultimately resulting in irreversible membrane damage.

2.2 System xc⁻–GSH–GPX4 Defense Axis

(1) SLC7A11 and Cystine Uptake

System xc⁻ is an important transport system for maintaining cellular resistance to ferroptosis, in which SLC7A11 mediates cystine/glutamate exchange. After entering cells, cystine is reduced to cysteine, providing a critical sulfur-containing substrate for GSH synthesis. SLC7A11 expression and transport activity therefore directly affect cellular reducing reserves and the ferroptosis threshold.

(2) GSH and GPX4

GPX4 uses the reducing capacity provided by GSH to convert membrane phospholipid hydroperoxides into the corresponding alcohols, thereby limiting lipid-radical chain reactions. Inhibition of SLC7A11, insufficient GSH synthesis, or loss of GPX4 function can disrupt this defense system, allowing phospholipid peroxides to accumulate continuously and drive ferroptosis.

2.3 Iron Homeostasis and Oxidizable Membrane Lipids

Ferroptosis is also controlled by the cellular labile iron pool and membrane-lipid composition. Increased bioavailable iron can promote oxidative reactions, whereas phospholipids containing polyunsaturated fatty acids such as arachidonic acid provide substrates for lipid peroxidation. Lipid-metabolic enzymes such as ACSL4 can influence the efficiency with which these PUFAs are incorporated into membrane phospholipids. When the rate of lipid-peroxide generation persistently exceeds the clearance capacity of GPX4 and other defense systems, cells enter ferroptosis.

3 Regulatory Relationship Between p53 and Ferroptosis

3.1 Molecular Basis of p53 Involvement in Ferroptosis

p53 is not a direct ferroptosis execution protein but alters cellular sensitivity by remodeling the metabolic environment required for ferroptosis. Its regulation can involve SLC7A11-mediated cystine uptake, GSH availability, polyamine metabolism, lipid oxidation, and stress adaptation. Therefore, the major role of p53 is to alter how readily cells cross the ferroptosis threshold rather than to establish an independent ferroptosis execution system.

3.2 Bidirectional Regulation of Ferroptosis by p53

(1) Pro-Ferroptotic Effects

Transcriptional repression of SLC7A11 by p53 can restrict cystine uptake and GSH synthesis, thereby weakening GPX4-dependent defense against lipid peroxidation. Under certain conditions, p53-induced SAT1 can additionally enhance ALOX15-related lipid oxidation. These two mechanisms act through reduced antioxidant defense and increased lipid oxidation, respectively, with the p53–SLC7A11 axis constituting the more central pro-ferroptotic mechanism.

(2) Inhibitory or Delaying Effects

p53 does not increase ferroptosis sensitivity in all cellular contexts. Under conditions such as cystine deprivation, the p53–p21 stress-response program can delay GSH depletion and ferroptosis progression. In specific tumor models, p53 can also restrict lipid peroxidation through DPP4-related mechanisms. The net effect of p53 on ferroptosis therefore depends on TP53 status, cell type, metabolic environment, and the relative strength of different downstream pathways.

4 Major Molecular Mechanisms by Which p53 Promotes Ferroptosis

4.1 p53–SLC7A11 Axis

(1) Transcriptional Repression of SLC7A11

p53 can reduce SLC7A11 transcriptional expression, thereby decreasing System xc⁻-mediated cystine uptake. Once cysteine availability becomes restricted, cellular GSH synthesis decreases and reducing reserves progressively decline.

(2) Weakening of GSH–GPX4 Defense

GSH deficiency limits the capacity of GPX4 to remove membrane phospholipid peroxides, allowing lipid peroxidation to accumulate more readily. Under conditions such as cystine restriction or Erastin treatment, p53-mediated SLC7A11 downregulation can further lower the ferroptosis threshold.

(3) Establishment of Ferroptosis Susceptibility

The core function of the p53–SLC7A11 axis is not to directly activate a cell-death execution protein but to weaken the cellular capacity to resist lipid peroxidation. When p53 activation is accompanied by decreased SLC7A11, reduced GSH, and increased lipid peroxidation, a relatively complete pro-ferroptotic mechanistic chain can be established.

4.2 p53–SAT1/ALOX15 Axis

(1) SAT1 and Polyamine Catabolism

SAT1 participates in acetylation and catabolism of Spermidine and Spermine and is also one of the metabolism-related targets regulated by p53. Increased SAT1 activity can alter polyamine homeostasis and the redox environment, providing conditions favorable for enhanced lipid oxidation.

(2) ALOX15-Related Lipid Oxidation

In some models, SAT1 upregulation can connect with ALOX15-related lipid oxidation and enhance membrane lipid peroxidation. This pathway can serve as a supplementary mechanism for p53-mediated ferroptosis, but its contribution is cell-context dependent, and ALOX15 should not be regarded as a universal execution factor in all forms of p53-dependent ferroptosis.

4.3 Differences from Classical p53 Tumor-Suppressive Programs

Regulation of ferroptosis by p53 can be partially separated from cell-cycle arrest and apoptosis. Some experimental models retain a degree of metabolic regulation and ferroptosis-sensitizing capacity even when classical p53-mediated cell-cycle or apoptotic functions are limited, indicating that p53-mediated redox and metabolic remodeling can itself constitute an important tumor-suppressive mechanism independent of classical apoptosis.

5 Context-Dependent Inhibition of Ferroptosis by p53

5.1 p53–p21 Axis

p53-induced CDKN1A/p21 can regulate not only the cell cycle but also cellular metabolic demand and adaptation to oxidative stress. In some cystine-deprivation models, the p53–p21 axis can delay glutathione depletion and lipid-peroxide accumulation, thereby postponing ferroptosis. Therefore, when p53 and p21 increase simultaneously, the direction of ferroptosis cannot be inferred from p53 levels alone and should instead be assessed together with SLC7A11, GSH, and lipid-peroxidation status.

5.2 p53–DPP4 Axis

In specific tumor contexts, the subcellular localization of DPP4 and its oxidase-related functions can influence membrane lipid peroxidation. Functional p53 can restrict DPP4-related pro-oxidative activity, whereas TP53 loss may promote DPP4 participation in membrane-associated oxidative processes and increase ferroptosis sensitivity. This mechanism is strongly tissue- and model-dependent and is mainly used to explain why p53 loss can paradoxically enhance ferroptosis under particular conditions.

5.3 Relative Importance of Bidirectional Effects

The p53–SLC7A11 axis is currently the more representative central mechanism for interpreting the pro-ferroptotic function of p53, while SAT1/ALOX15 provides a supplementary mechanism at the level of lipid oxidation. In contrast, p53–p21 and p53–DPP4 indicate that p53 can exert protective effects under specific metabolic and tissue contexts. Therefore, wild-type TP53 status or elevated p53 expression alone cannot predict cellular ferroptosis sensitivity.

Table 1 Major Molecular Axes Through Which p53 Regulates Ferroptosis

6 TP53 Status and Ferroptosis Sensitivity

6.1 Wild-Type TP53

Wild-type TP53 provides the basis for complete p53 transcriptional regulatory function but does not independently determine ferroptosis sensitivity. When SLC7A11 repression or SAT1-related lipid oxidation predominates, p53 can lower the ferroptosis threshold; when protective responses such as p21 predominate, cells may instead display delayed ferroptosis. Wild-type TP53 therefore represents a mechanistic background rather than a single predictive marker.

6.2 TP53 Loss

TP53 loss can eliminate part of the p53-dependent regulation of SLC7A11 and SAT1, but ferroptosis does not necessarily decrease. Other networks, including GPX4, FSP1, ACSL4, iron homeostasis, and DPP4, can still determine cellular responses. Some TP53-deficient models may even display increased ferroptosis sensitivity because of DPP4-related lipid oxidation or other compensatory changes.

6.3 TP53 Mutation

TP53 mutation is not equivalent to complete loss of p53. Different mutations can cause reduced DNA-binding capacity, partial loss of transcriptional function, dominant-negative effects, or gain-of-function properties. Consequently, the effects of different mutants on SLC7A11, redox homeostasis, and lipid metabolism can vary substantially. Ferroptosis experiments should therefore define the specific TP53 genotype and verify p53 status using functional downstream indicators.

7 Pharmacological Investigation and Interpretation of the p53–Ferroptosis Axis

7.1 Validation of p53 Functional Dependence

MDM2 antagonists such as Nutlin-3a, Nutlin-3, and RG7388 can increase the stability of functional p53, whereas p53 inhibitory tools such as Pifithrin-α can provide reverse validation. Experiments should assess SLC7A11, p21, and lipid-peroxidation levels to determine the actual effects of p53 activation rather than inferring enhanced ferroptosis solely from increased p53 protein.

7.2 Localization of the Ferroptosis Regulatory Node

Erastin mainly interferes with System xc⁻-related cystine utilization and limits GSH supply, whereas RSL3 directly inhibits GPX4 function. If TP53 status primarily affects sensitivity to Erastin but has limited effects on RSL3 responses, this suggests that p53 acts more strongly upstream at the SLC7A11–GSH level. If responses to both classes of inducers change substantially, lipid metabolism, iron homeostasis, and other antioxidant defense mechanisms should also be considered.

7.3 Validation of the Ferroptosis Mechanism

Ferroptosis determination should center on evidence of lipid peroxidation and specific rescue. Ferrostatin-1 or Liproxstatin-1 can inhibit lipid-radical chain reactions, while Deferoxamine can validate iron dependence by reducing the labile iron pool. Reduced cell viability or increased total ROS alone cannot establish ferroptosis and should be interpreted together with lipid peroxidation, SLC7A11–GSH–GPX4 status, and rescue results.

7.4 TP53 Status and Result Interpretation

Wild-type, deleted, and different mutant forms of TP53 do not have equivalent p53 functions, and p53 protein abundance does not directly represent transcriptional activity. Results should be interpreted together with TP53 genotype, p53 functional status, and downstream indicators such as SLC7A11 and p21. In particular, the pro-ferroptotic effect of p53–SLC7A11 should be distinguished from the protective p53–p21 response to determine the dominant regulatory direction in different cellular contexts.

8 Products Related to p53 and Ferroptosis Research

8.1 Products for p53/MDM2 Regulation and p53 Functional Research

8.2 Products Related to p53–Ferroptosis Crosstalk Pathways

8.3 Products Related to Ferroptosis Induction and Mechanistic Validation

p53 connects classical tumor suppression with ferroptosis through transcriptional regulation and metabolic remodeling. The p53–SLC7A11 axis represents a relatively central pro-ferroptotic mechanism, SAT1/ALOX15 provides a supplementary lipid-oxidation pathway, whereas p21- and DPP4-related pathways reflect context-dependent protective functions. Investigation of the p53–ferroptosis axis should simultaneously consider TP53 genotype, p53 functional status, System xc⁻–GSH–GPX4 defense, and evidence of lipid peroxidation to avoid mechanistic attribution based solely on p53 expression or a single cell-death indicator.

References

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[4] Xiaolei Zhou, Galina Selivanova, et al. Pharmacological activation of p53 triggers viral mimicry response thereby abolishing tumor immune evasion and promoting anti-tumor immunity. Cancer Discov. 2021 Jul 6;candisc.1741.2020.

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