Evidence map›Paper›PMID 40070026›Full record

ArticleClinical and translational medicine2025

p53 inhibits OTUD5 transcription to promote GPX4 degradation and induce ferroptosis in gastric cancer.

Junjing Zhang, Tongguan Tian, Xinxing Li, Kai Xu, Yao Lu, Xia Li, Xinyu Zhao, Ziyi Cui, Zhenxiang Wang, Yuefan Zhou and 6 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Clinical and translational medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.

0numbers the graph read from it
0cells of the map it votes in
13citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

13 citing papers in PubMed.

  1. Article
  2. Silencing of MAT2A inhibits gastric cancer cell proliferation, migration, and invasion through activation of the p53 pathway.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026
    Article
  3. Article
  4. Review
  5. Article
  6. Review
  7. Review
  8. Research progress on ferroptosis in drug resistance and therapy of gastric cancer.Journal of cancer research and clinical oncology · 2025
    Review
  9. Article
  10. Review
  11. Article
  12. Review
  13. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors.

Junjing ZhangDepartment of Gastrointestinal Surgery, Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Tongguan TianDepartment of Gastrointestinal Surgery, Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Xinxing LiDepartment of Gastrointestinal Surgery, Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Kai XuDepartment of Gastrointestinal Surgery, Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Yao LuInternational & Talent Office, Tongji Hospital, Tongji University, Shanghai, China.
Xia LiDepartment of Gastrointestinal Surgery, Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Xinyu ZhaoDepartment of Gastrointestinal Surgery, Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Ziyi CuiDepartment of Gastrointestinal Surgery, Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Zhenxiang WangDepartment of Gastrointestinal Surgery, Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Yuefan ZhouDepartment of Gastrointestinal Surgery, Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Yixin XuDepartment of Gastrointestinal Surgery, Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Hongchen LiDepartment of Gastrointestinal Surgery, Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Yan ZhangDepartment of Gastrointestinal Surgery, Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.ORCID 0000-0001-9795-0827
Yu DuDepartment of Gastrointestinal Surgery, Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Lei LvDepartment of Biochemistry and Molecular Biology, MOE Key Laboratory of Metabolism and Molecular Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Yanping XuDepartment of Gastrointestinal Surgery, Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.ORCID 0009-0007-0890-4820

Funding

National Key R&D Program of China 2022YFA0807100National Natural Science Foundation of ChinaShanghai Rising-Star Programthe Fundamental Research Funds for the Central Universities
6 · The paper itself

Abstract

backgroundGastric cancer is one of the most prevalent malignant tumors within the digestive system, and ferroptosis playing a crucial role in its progression. Glutathione peroxidase 4 (GPX4), a key negative regulator of ferroptosis, is highly expressed in gastric cancer and contributes to tumor growth. Targeting the regulation of GPX4 has emerged as a promising approach to induce ferroptosis and develop effective therapy for gastric cancer.

methodsTo confirm that OTUD5 is a deubiquitinase of GPX4 and regulates ferroptosis, we performed Western blotting, Co-IP, immunofluorescence, quantitative real-time PCR, Ub assay and flow cytometry experiments. To explore the physiological function of OUTD5, we knocked out the Otud5 gene in the mouse gastric cancer cell line (MFC) using CRISPR-Cas9 and eatablished the subcutaneous tumour model. Immunohistochemistry (IHC) analysis was used to inveatigate the pathological correlation in human gastric cancer.

resultsWe report that ovarian tumor domain-containing 5 (OTUD5) interacts with, deubiquitylates and stabilizes GPX4. OTUD5 depletion destabilizes GPX4, promotes lipid peroxidation and sensitizes gastric cancer cells to ferroptosis. Moreover, the p53 activator nutlin-3a suppresses OTUD5 transcription, leading to GPX4 degradation and ferroptosis of gastric cancer cells. Notably, only wild-type p53 has the capacity to inhibit OTUD5 transcription, while p53 mutations or deficiencies correlate with increased OTUD5 expression, promoting gastric cancer progression. Additionally, OTUD5 silencing and nutlin-3a-induced GPX4 degradation enhances the sensitivity of gastric cancer cells to ferroptosis in vivo. Subsequently, the p53/OTUD5/GPX4 axis is confirmed in clinical gastric cancer samples.

conclusionCollectively, these findings elucidate a mechanism whereby p53 inactivation upregulates OTUD5 transcription to deubiquitylate and stablize GPX4, resulting in ferroptosis inhibition and gastric cancer progression. This discovery highlights the potential therapeutic value of targeting OTUD5 to promote ferroptosis in p53-inactivated gastric cancer. KEY POINTS: OTUD5 mediates GPX4 deubiquitination to regulate its stability. Deletion of OTUD5 promotes ferroptosis and inhibits tumor growth. Wild type p53 inhibits OTUD5 transcription, thereby promoting GPX4 degradation and inhibiting the development of gastric cancer. OTUD5, GPX4 expression and p53 activity are highly correlated and correlates with clinical progression in STAD.

Indexed as

FerroptosisPhospholipid Hydroperoxide Glutathione PeroxidaseStomach NeoplasmsTumor Suppressor Protein p53AnimalsCell Line, TumorHumansMicePhospholipid Hydroperoxide Glutathione PeroxidaseTumor Suppressor Protein p53deubiquitinaseferroptosisGPX4OTUD5p53

Identifiers

PMID40070026
PMCPMC11897053

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.