Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Hypoxia inhibits ferritinophagy-mediated ferroptosis in esophageal squamous cell carcinoma via the USP2-NCOA4 axis

Oncogene volume 43, pages 2000–2014 (2024)Cite this article

Subjects

A Correction to this article was published on 27 June 2025

This article has been updated

Abstract

Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy of the digestive system. Hypoxia is a crucial player in tumor ferroptosis resistance. However, the molecular mechanism of hypoxia-mediated ferroptosis resistance in ESCC remains unclear. Here, USP2 expression was decreased in ESCC cell lines subjected to hypoxia treatment and was lowly expressed in clinical ESCC specimens. Ubiquitin-specific protease 2 (USP2) depletion facilitated cell growth, which was blocked in USP2-overexpressing cells. Moreover, USP2 silencing enhanced the iron ion concentration and lipid peroxidation accumulation as well as suppressed ferroptosis, while upregulating USP2 promoted ferroptotic cell death in ESCC cells. Furthermore, knockout of USP2 in ESCC models discloses the essential role of USP2 in promoting ESCC tumorigenesis and inhibiting ferroptosis. In contrast, overexpression of USP2 contributes to antitumor effect and ferroptosis events in vivo. Specifically, USP2 stably bound to and suppressed the degradation of nuclear receptor coactivator 4 (NCOA4) by eliminating the Lys48-linked chain, which in turn triggered ferritinophagy and ferroptosis in ESCC cells. Our findings suggest that USP2 plays a crucial role in iron metabolism and ferroptosis and that the USP2/NCOA4 axis is a promising therapeutic target for the management of ESCC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Hypoxia is negatively correlated with ferroptosis in ESCC cells.
Fig. 2: Hypoxia promotes ferroptosis resistance in ESCC.
Fig. 3: USP2 is downregulated in hypoxic ESCC cells.
Fig. 4: Upregulation of USP2 facilitates ferroptosis in ESCC cells.
Fig. 5: USP2-driven ferroptotic cell death correlates with activation of autophagy.
Fig. 6: USP2 interacts with NCOA4.
Fig. 7: USP2 blcoks NCOA4 ubiquitination.
Fig. 8: USP2 regulates ESCC tumorigenesis in vivo.

Similar content being viewed by others

Data availability

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

Change history

  • 27 June 2025

    The original online version of this article was revised: Following the publication of this article, the authors noted that the KYSE410 USP2 image in Figure 5E was mistakenly duplicated with the KYSE150 shNC image in Figure 5E. Additionally, the KYSE150 image 2 in Figure S8G was mistakenly duplicated with the KYSE410 image 4 in Figure 4C. The authors also noted an error in the textual description in the Abstract section. The corrected version is as follows: “Moreover, USP2 silencing decreased the iron ion concentration and lipid peroxidation accumulation as well as suppressed ferroptosis, while upregulating USP2 promoted ferroptotic cell death in ESCC cells.” Furthermore, figure legends for tumor weight data (Figure 8H and Figure S12C) have been revised to clarify that the error bars represent the means with 95% confidence intervals, rather than standard deviations (SD) as previously stated. The corrected versions are as follows:

    Fig. 8 USP2 regulates ESCC tumorigenesis in vivo

    (H) Representative images of tumors and quantification of tumor weights in nude mice bearing ESCC cells in indicated groups (n = 3). Data are presented as the means with 95% confidence intervals from three independent experiments.

    Fig. S12 USP2 regulates ESCC tumorigenesis in vivo

    (C) Representative images of tumors and quantification of tumor weights in nude mice bearing ESCC cells in indicated groups (n = 3). Data are presented as the means with 95% confidence intervals from three independent experiments.

    The authors confirm this correction does not affect the conclusions of the paper and apologize for any inconvenience caused. The original article has been corrected.

  • 27 June 2025

    A Correction to this paper has been published: https://doi.org/10.1038/s41388-025-03443-8

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. Abnet CC, Arnold M, Wei WQ. Epidemiology of esophageal squamous cell carcinoma. Gastroenterology. 2018;154:360–73.

    Article  PubMed  Google Scholar 

  3. Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med. 2003;349:2241–52.

    Article  CAS  PubMed  Google Scholar 

  4. Zhu H, Ma X, Ye T, Wang H, Wang Z, Liu Q, et al. Esophageal cancer in China: practice and research in the new era. Int J Cancer. 2023;152:1741–51.

    Article  CAS  PubMed  Google Scholar 

  5. Jing X, Yang F, Shao C, Wei K, Xie M, Shen H, et al. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer. 2019;18:157.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Wicks EE, Semenza GL. Hypoxia-inducible factors: cancer progression and clinical translation. J Clin Invest. 2022;132:e159839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ivan M, Fishel ML, Tudoran OM, Pollok KE, Wu X, Smith PJ. Hypoxia signaling: challenges and opportunities for cancer therapy. Semin Cancer Biol. 2022;85:185–95.

    Article  CAS  PubMed  Google Scholar 

  8. Lin Z, Song J, Gao Y, Huang S, Dou R, Zhong P, et al. Hypoxia-induced HIF-1α/lncRNA-PMAN inhibits ferroptosis by promoting the cytoplasmic translocation of ELAVL1 in peritoneal dissemination from gastric cancer. Redox Biol. 2022;52:102312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Xiong J, Nie M, Fu C, Chai X, Zhang Y, He L, et al. Hypoxia enhances HIF1α transcription activity by upregulating KDM4A and mediating H3K9me3, thus inducing ferroptosis resistance in cervical cancer cells. Stem Cells Int. 2022;2022:1608806.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Fan Z, Yang G, Zhang W, Liu Q, Liu G, Liu P, et al. Hypoxia blocks ferroptosis of hepatocellular carcinoma via suppression of METTL14 triggered YTHDF2-dependent silencing of SLC7A11. J Cell Mol Med. 2021;25:10197–212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lei G, Zhuang L, Gan B. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer. 2022;22:381–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mou Y, Wang J, Wu J, He D, Zhang C, Duan C, et al. Ferroptosis, a new form of cell death: opportunities and challenges in cancer. J Hematol Oncol. 2019;12:34.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Chen X, Kang R, Kroemer G, Tang D. Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol. 2021;18:280–96.

    Article  CAS  PubMed  Google Scholar 

  14. Liang C, Zhang X, Yang M, Dong X. Recent progress in ferroptosis inducers for cancer therapy. Adv Mater. 2019;31:e1904197.

    Article  PubMed  Google Scholar 

  15. Tang D, Chen X, Kang R, Kroemer G. Ferroptosis: molecular mechanisms and health implications. Cell Res. 2021;31:107–25.

    Article  CAS  PubMed  Google Scholar 

  16. Ajoolabady A, Aslkhodapasandhokmabad H, Libby P, Tuomilehto J, Lip GYH, Penninger JM, et al. Ferritinophagy and ferroptosis in the management of metabolic diseases. Trends Endocrinol Metab. 2021;32:444–62.

    Article  CAS  PubMed  Google Scholar 

  17. Friedmann Angeli JP, Krysko DV, Conrad M. Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion. Nat Rev Cancer. 2019;19:405–14.

    Article  CAS  PubMed  Google Scholar 

  18. Rodriguez R, Schreiber SL, Conrad M. Persister cancer cells: Iron addiction and vulnerability to ferroptosis. Mol Cell. 2022;82:728–40.

    Article  CAS  PubMed  Google Scholar 

  19. Tu Y, Xu L, Xu J, Bao Z, Tian W, Ye Y, et al. Loss of deubiquitylase USP2 triggers development of glioblastoma via TGF-β signaling,. Oncogene. 2022;41:2597–608.

    Article  CAS  PubMed  Google Scholar 

  20. Zhu L, Chen Z, Guo T, Chen W, Zhao L, Guo L, et al. USP2 Inhibits Lung Cancer Pathogenesis by Reducing ARID2 Protein Degradation via Ubiquitination. Biomed Res Int. 2022;2022:1525216.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Xiao W, Wang J, Wang X, Cai S, Guo Y, Ye L, et al. Therapeutic targeting of the USP2-E2F4 axis inhibits autophagic machinery essential for zinc homeostasis in cancer progression. Autophagy. 2022;18:2615–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gao M, Monian P, Pan Q, Zhang W, Xiang J, Jiang X. Ferroptosis is an autophagic cell death process. Cell Res. 2016;26:1021–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhou B, Liu J, Kang R, Klionsky DJ, Kroemer G, Tang D. Ferroptosis is a type of autophagy-dependent cell death. Semin Cancer Biol. 2020;66:89–100.

    Article  CAS  PubMed  Google Scholar 

  24. Mennerich D, Kubaichuk K, Kietzmann T. DUBs, hypoxia, and cancer. Trends Cancer. 2019;5:632–53.

    Article  CAS  PubMed  Google Scholar 

  25. Yang H, Hu Y, Weng M, Liu X, Wan P, Hu Y, et al. Hypoxia inducible lncRNA-CBSLR modulates ferroptosis through m6A-YTHDF2-dependent modulation of CBS in gastric cancer. J Adv Res. 2022;37:91–106.

    Article  CAS  PubMed  Google Scholar 

  26. Sun S, Guo C, Gao T, Ma D, Su X, Pang Q, et al. Hypoxia enhances glioma resistance to sulfasalazine-induced ferroptosis by upregulating SLC7A11 via PI3K/AKT/HIF-1α axis. Oxid Med Cell Longev. 2022;2022:7862430.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chen Z, Han F, Du Y, Shi H, Zhou W. Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2023;8:70.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Liao C, Liu X, Zhang C, Zhang Q. Tumor hypoxia: from basic knowledge to therapeutic implications. Semin Cancer Biol. 2023;88:172–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tang Z, Jiang W, Mao M, Zhao J, Chen J, Cheng N. Deubiquitinase USP35 modulates ferroptosis in lung cancer via targeting ferroportin. Clin Transl Med. 2021;11:e390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Meng C, Zhan J, Chen D, Shao G, Zhang H, Gu W, et al. The deubiquitinase USP11 regulates cell proliferation and ferroptotic cell death via stabilization of NRF2 USP11 deubiquitinates and stabilizes NRF2. Oncogene. 2021;40:1706–20.

    Article  CAS  PubMed  Google Scholar 

  31. Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ 3rd, et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy. 2016;12:1425–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jain V, Amaravadi RK. Pumping iron: ferritinophagy promotes survival and therapy resistance in pancreatic cancer. Cancer Discov. 2022;12:2023–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li C, Zhang J, Xu H, Chang M, Lv C, Xue W, et al. Retigabine ameliorates acute stress-induced impairment of spatial memory retrieval through regulating USP2 signaling pathways in hippocampal CA1 area. Neuropharmacology. 2018;135:151–62.

    Article  CAS  PubMed  Google Scholar 

  35. Latunde-Dada GO. Ferroptosis: Role of lipid peroxidation, iron and ferritinophagy. Biochim Biophys Acta Gen Subj. 2017;1861:1893–1900.

    Article  CAS  PubMed  Google Scholar 

  36. Li K, Chen B, Xu A, Shen J, Li K, Hao K, et al. TRIM7 modulates NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells. Redox Biol. 2022;56:102451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank the Core Facility of Jiangsu Provincial People’s Hospital for its help in the detection of experimental samples.

Funding

This work was supported by the Natural Science Foundation of Jiangsu Province (BK20201080), and the National Natural Science Foundation of China (82003228, 82003235, 82102830, 82102831), and the Research project of clinical medical science and technology development fund of Jiangsu University (No:JLY2021097), and the Court-level Natural Science Foundation Project of Jurong People’s Hospital (Nos. JY20221001, JY20231005).

Author information

Author notes

  1. These authors contributed equally: Jiahang Song, Junfeng Zhang.

Authors and Affiliations

  1. Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

    Jiahang Song, Qing Gao, Hui Chen, Xiaofeng Ding, Minghui Zhao, Xinchen Sun & Xiaoke Di

  2. Department of Radiology, General Hospital of Western Theater Command, Chengdu, 600083, China

    Junfeng Zhang

  3. Department of Oncology, Jurong People’s Hospital Affiliated to Jiangsu University, Huayang Town, Jurong, 212400, China

    Yujing Shi, Caiqiang Zhu & Liang Liang

  4. Department of Radiology, Suzhou 100 Hospital, Suzhou, 215000, China

    Yingyin Zhu

  5. Chongqing Municipal Health and Health Committee, Chongqing, 400042, China

    Wei Wang

  6. Cancer Center, Army Medical Center, Chongqing, 400042, China

    Qing Li

Authors
  1. Jiahang Song
    View author publications

    Search author on:PubMed Google Scholar

  2. Junfeng Zhang
    View author publications

    Search author on:PubMed Google Scholar

  3. Yujing Shi
    View author publications

    Search author on:PubMed Google Scholar

  4. Qing Gao
    View author publications

    Search author on:PubMed Google Scholar

  5. Hui Chen
    View author publications

    Search author on:PubMed Google Scholar

  6. Xiaofeng Ding
    View author publications

    Search author on:PubMed Google Scholar

  7. Minghui Zhao
    View author publications

    Search author on:PubMed Google Scholar

  8. Caiqiang Zhu
    View author publications

    Search author on:PubMed Google Scholar

  9. Liang Liang
    View author publications

    Search author on:PubMed Google Scholar

  10. Xinchen Sun
    View author publications

    Search author on:PubMed Google Scholar

  11. Yingyin Zhu
    View author publications

    Search author on:PubMed Google Scholar

  12. Wei Wang
    View author publications

    Search author on:PubMed Google Scholar

  13. Qing Li
    View author publications

    Search author on:PubMed Google Scholar

  14. Xiaoke Di
    View author publications

    Search author on:PubMed Google Scholar

Contributions

JS, XD, JZ and QL contributed to the design of the study. JS, JZ, YS, and QG performed the experiments. HC, MZ, CZ and LL analyzed and interpreted the data. JZ, YZ and WW prepared all figures. JS, XD, JZ and QL contributed to the writing and revision of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Wei Wang, Qing Li or Xiaoke Di.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Song, J., Zhang, J., Shi, Y. et al. Hypoxia inhibits ferritinophagy-mediated ferroptosis in esophageal squamous cell carcinoma via the USP2-NCOA4 axis. Oncogene 43, 2000–2014 (2024). https://doi.org/10.1038/s41388-024-03050-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41388-024-03050-z

This article is cited by

Search

Advanced search

Quick links