Ferroptosis as a p53-mediated activity during tumour suppression
Open accessAbstract
Although p53-mediated cell-cycle arrest, senescence and apoptosis serve as critical barriers to cancer development, emerging evidence suggests that the metabolic activities of p53 are also important. Here we show that p53 inhibits cystine uptake and sensitizes cells to ferroptosis, a non-apoptotic form of cell death, by repressing expression of SLC7A11, a key component of the cystine/glutamate antiporter. Notably, p53(3KR), an acetylation-defective mutant that fails to induce cell-cycle arrest, senescence and apoptosis, fully retains the ability to regulate SLC7A11 expression and induce ferroptosis upon reactive oxygen species (ROS)-induced stress. Analysis of mutant mice shows that these non-canonical p53 activities contribute to embryonic development and the lethality associated with loss of Mdm2. Moreover, SLC7A11 is highly expressed in human tumours, and its overexpression inhibits ROS-induced ferroptosis and abrogates p53(3KR)-mediated tumour growth suppression in xenograft models. Our findings uncover a new mode of tumour suppression based on p53 regulation of cystine metabolism, ROS responses and ferroptosis.
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p53 directly inhibits the transcription of SLC7A11, a key transporter of cysteine that imports extracellular cystine into cells.
“p53 directly inhibits the transcription of SLC7A11, a key transporter of cysteine that imports extracellular cystine into cells37.”
From An HDAC4-specific PROTAC degrader achieves radiation sensitization by enhancing ferroptosis in lung cancer (2026) · cites this paper as [37]
Suppression of SLC7A11 by p53 contributes to the tumor suppressive activity of p53.
“Furthermore, this suppression was suggested to contribute to the tumor suppressive activity of p53”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [75]
p53 can activate ferroptosis by suppressing expression of SLC7A11, a component of system xc−.
“A recent study reported that p53 can activate ferroptosis by suppressing the expression of SLC7A11, a component of system xc− [75].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [75]
Ferroptosis was recently shown to be executed via the tumor suppressor p53, suggesting a natural anti-tumor role of ferroptosis.
“This type of cell death was recently shown to be executed via the tumor suppressor p53 [162,163], suggesting a natural anti-tumor role of ferroptosis.”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [163]
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- Authors
- Jiang, L., Kon, N., Li, T., Wang, S.-J., Su, T., Hibshoosh, H., Baer, R., & Gu, W.
- Affiliations
- Columbia University (US)
- Herbert Irving Comprehensive Cancer Center (US)
- Corresponding author
- Gu, Wei
- Venue
- Nature
- Published
- 2015-03-18
- Volume
- 520
- Issue
- 7545
- Pages
- 57-62
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4455927
- OpenAlex
- W2067107606
- Cited by
- 3,398
- References
- 39
- Citations by year
- 2026: 352 · 2025: 509 · 2024: 539 · 2023: 542 · 2022: 500 · 2021: 355 · 2020: 200 · 2019: 123 · 2018: 95 · 2017: 83 · 2016: 67 · 2015: 25 · 2014: 1
- FWCI
- 71.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (2r01ca085533-16)
- National Cancer Institute (R01CA166294, R01-CA085533, P01CA097403, R01CA172272, R01CA169246, T32 CA 09503, P01CA080058, T32CA009503, R01CA172023)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- ferroptosis, p53, SLC7A11, cystine uptake, tumor suppression, reactive oxygen species, p53 acetylation, MDM2, iron-dependent cell death, cystine metabolism
- MeSH terms
- Animals, Biological Transport, Cystine, Embryo, Mammalian, Humans, Iron, Neoplasms, Substrate Specificity, Tumor Suppressor Protein p53, Cell Death, Reactive Oxygen Species, Oxidative Stress, Xenograft Model Antitumor Assays, Amino Acid Transport System y+, Embryonic Development, Mice, Proto-Oncogene Proteins c-mdm2
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