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Targeting the ODC1-YBX1 axis reverses gastric cancer chemoresistance via transcriptional control of SLC7A11-mediated ferroptosis
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  • Published: 14 April 2026

Targeting the ODC1-YBX1 axis reverses gastric cancer chemoresistance via transcriptional control of SLC7A11-mediated ferroptosis

  • Ruiqi Li1,3,4,
  • Shantanu Baral2,3,4,
  • Fanyu Zhao2,3,4,
  • Chenkai Zhang2,3,4,
  • Jiajie Zhou1,3,4,
  • Ben Li1,3,4,
  • Yifan Cheng1,3,4,
  • Dengyang Fang2,3,4,
  • Zijie Xu1,3,4,
  • Yayan Fu2,3,4,
  • Jianyue Ding2,3,4,
  • Zhen Tian1,3,4,
  • Shuai Zhao1,3,4,
  • Jie Wang2,3,4,
  • Mengli Zi1,3,4,
  • Longhe Sun2,3,4,
  • Xuetong Jiang5,
  • Qiannan Sun3,4 &
  • …
  • Daorong Wang1,3,4 

Cell Death Discovery , Article number:  (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Chemotherapy
  • Gastric cancer

Abstract

Gastric adenocarcinoma (STAD), a leading cause of cancer mortality, faces major therapeutic challenges due to intrinsic and acquired chemoresistance. Chemoresistance is intricately linked to ferroptosis.Elucidating the mechanisms of chemotherapy resistance in STAD represents a critical unmet need to improve patient survival. This study identifies ODC1 as a crucial driver of 5-Fu resistance and suppressor of ferroptosis in STAD. Multi-dataset analysis revealed significant ODC1 overexpression in STAD tissues, correlating with advanced stage and poor survival. Functionally, ODC1 depletion inhibited proliferation, migration, invasion, and tumor growth in vitro and in vivo, while its overexpression exacerbated malignant phenotypes. Critically, ODC1 was upregulated in 5-Fu-resistant cell models, and its knockdown restored chemosensitivity by triggering ferroptosis—an iron-dependent cell death characterized by lipid peroxidation, glutathione depletion, and malondialdehyde accumulation. Mechanistically, ODC1 interacts with transcription factor YBX1 through its PLPDE_III_ODC domain. This complex binds the promoter of SLC7A11, enhancing its transcription. YBX1 silencing phenocopied ODC1 knockdown, increasing ferroptosis susceptibility; conversely, SLC7A11 overexpression or GPX4 activation (via ML334) reversed ferroptosis induced by ODC1/YBX1 inhibition. Significantly, Erastin—a SLC7A11 inhibitor—overcame YBX1-mediated resistance, synergizing with 5-Fu to induce ferroptosis and suppress tumor growth. Collectively, we unveil the ODC1-YBX1-SLC7A11-ferroptosis axis as a central mechanism of chemoresistance in STAD. Targeting this axis—via ODC1 inhibition or ferroptosis induction—represents a novel therapeutic strategy to reverse treatment resistance in gastric adenocarcinoma.

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Data availability

The datasets generated and/or analysed during the current study are not publicly available due to patient privacy concerns but are available from the corresponding author on reasonable request.The transcriptome sequencing data have been uploaded to a public database.https://ngdc.cncb.ac.cn/gsa-human/browse/HRA016361.

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Acknowledgements

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Funding

This study was financially supported by National Natural Science Foundation of China (NO.82373014).

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Authors and Affiliations

  1. Northern Jiangsu People’s Hospital, Clinical Teaching Hospital of Medical School, Nanjing University, Yangzhou, China

    Ruiqi Li, Jiajie Zhou, Ben Li, Yifan Cheng, Zijie Xu, Zhen Tian, Shuai Zhao, Mengli Zi & Daorong Wang

  2. Medical College of Yangzhou University, Yangzhou, China

    Shantanu Baral, Fanyu Zhao, Chenkai Zhang, Dengyang Fang, Yayan Fu, Jianyue Ding, Jie Wang & Longhe Sun

  3. Northern Jiangsu People’s Hospital, Yangzhou, China

    Ruiqi Li, Shantanu Baral, Fanyu Zhao, Chenkai Zhang, Jiajie Zhou, Ben Li, Yifan Cheng, Dengyang Fang, Zijie Xu, Yayan Fu, Jianyue Ding, Zhen Tian, Shuai Zhao, Jie Wang, Mengli Zi, Longhe Sun, Qiannan Sun & Daorong Wang

  4. Yangzhou Key Laboratory of Basic and Clinical Transformation of Digestive and Metabolic Diseases, Yangzhou, China

    Ruiqi Li, Shantanu Baral, Fanyu Zhao, Chenkai Zhang, Jiajie Zhou, Ben Li, Yifan Cheng, Dengyang Fang, Zijie Xu, Yayan Fu, Jianyue Ding, Zhen Tian, Shuai Zhao, Jie Wang, Mengli Zi, Longhe Sun, Qiannan Sun & Daorong Wang

  5. The YangZhou Clinical College of Xuzhou Medical University, Xuzhou, China

    Xuetong Jiang

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Contributions

Conceptualization: Ruiqi Li, Jiajie Zhou, Chenkai Zhang; Shantanu Baral, Data production, analysis and investigation: Ruiqi Li, Fanyu Zhao, Yifan Cheng, Zijie Xu, Shuai Zhao, Jie Wang, Yayan Fu, Longhe Sun, Zhen Tian, Chenkai Zhang, Xuetong Jiang, Mengli Zi; Writing, Review and Edit: Ruiqi Li, Jianyue Ding,Dengyang Fang, Ben Li, Qiannan Sun; Supervision: Ruiqi Li. Funding acquisition: Daorong Wang. The author(s) read and approved the final manuscript.

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This study was approved by the Ethics Committee of Northern Jiangsu People’s Hospital, and written informed consent was obtained from all participants. All animal procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of Yangzhou University (Approval No. 202303827).

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Li, R., Baral, S., Zhao, F. et al. Targeting the ODC1-YBX1 axis reverses gastric cancer chemoresistance via transcriptional control of SLC7A11-mediated ferroptosis. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03067-1

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  • Received: 16 December 2025

  • Revised: 13 February 2026

  • Accepted: 09 March 2026

  • Published: 14 April 2026

  • DOI: https://doi.org/10.1038/s41420-026-03067-1

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