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Background <p>5-Fluorouracil (5-FU) remains a cornerstone of first-line chemotherapy for gastric cancer, yet the emergence of resistance severely compromises its clinical efficacy. Although ferroptosis suppression has been recognized as a pivotal mechanism of chemoresistance, the mitochondrial regulatory processes involved remain poorly understood.</p> Methods <p>We integrated clinical specimen analysis, in vitro and in vivo functional assays, multi-omics profiling, and molecular docking to delineate the role of the mitochondrial oxidoreductase OXNAD1 in mediating 5-FU resistance in gastric cancer, and to assess the therapeutic potential of the natural polyphenol resveratrol as a chemosensitizing agent.</p> Results <p>OXNAD1 was found to be significantly overexpressed in gastric cancer tissues and cell lines, correlating with unfavorable prognosis and enhanced 5-FU resistance. Mechanistically, OXNAD1 directly bound to and suppressed the ferroptosis driver PTGS2, thereby attenuating lipid peroxidation and mitochondrial damage, ultimately restraining ferroptosis and promoting drug resistance. Notably, resveratrol disrupted the OXNAD1–PTGS2 interaction by directly binding OXNAD1, reinstating ferroptotic activity, markedly enhancing the cytotoxic effect of 5-FU in resistant cells, and potentiating the antitumor efficacy of 5-FU in xenograft models.</p> Conclusion <p>The OXNAD1–PTGS2 axis constitutes a critical metabolic–cell death cross-regulatory pathway underlying 5-FU resistance in gastric cancer. Targeting this axis with resveratrol provides a promising combinatorial strategy to overcome chemoresistance.</p> Graphical Abstract <p></p>

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Targeting the OXNAD1–PTGS2 axis with resveratrol overcomes ferroptosis Inhibition and reverses 5-FU resistance in gastric cancer

  • 期刊论文

  • 发表日期：

    2026年3月13日

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  • Jinzhou Wang,
  • Bishuang Xu,
  • Xiaohan Lin,
  • Biyu Chen,
  • Xiaoyan Liu,
  • Wei Wu

摘要

Background

5-Fluorouracil (5-FU) remains a cornerstone of first-line chemotherapy for gastric cancer, yet the emergence of resistance severely compromises its clinical efficacy. Although ferroptosis suppression has been recognized as a pivotal mechanism of chemoresistance, the mitochondrial regulatory processes involved remain poorly understood.

Methods

We integrated clinical specimen analysis, in vitro and in vivo functional assays, multi-omics profiling, and molecular docking to delineate the role of the mitochondrial oxidoreductase OXNAD1 in mediating 5-FU resistance in gastric cancer, and to assess the therapeutic potential of the natural polyphenol resveratrol as a chemosensitizing agent.

Results

OXNAD1 was found to be significantly overexpressed in gastric cancer tissues and cell lines, correlating with unfavorable prognosis and enhanced 5-FU resistance. Mechanistically, OXNAD1 directly bound to and suppressed the ferroptosis driver PTGS2, thereby attenuating lipid peroxidation and mitochondrial damage, ultimately restraining ferroptosis and promoting drug resistance. Notably, resveratrol disrupted the OXNAD1–PTGS2 interaction by directly binding OXNAD1, reinstating ferroptotic activity, markedly enhancing the cytotoxic effect of 5-FU in resistant cells, and potentiating the antitumor efficacy of 5-FU in xenograft models.

Conclusion

The OXNAD1–PTGS2 axis constitutes a critical metabolic–cell death cross-regulatory pathway underlying 5-FU resistance in gastric cancer. Targeting this axis with resveratrol provides a promising combinatorial strategy to overcome chemoresistance.

Graphical Abstract