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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月14日

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  • 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,
  • Xuetong Jiang,
  • Qiannan Sun,
  • Daorong Wang

摘要

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.