Reading view
BRD4 Inhibition Mitigates Acute and Chronic Corneal Injury Following Topical Nitrogen Mustard Exposure
MITF-SCD1 Lipid Metabolic Axis Prevents Ouabain-Induced Spiral Ganglion Neuron Ferroptosis and Hearing Loss
Genetic predictors of GLP1 receptor agonist weight loss and side effects
Nature, Published online: 08 April 2026; doi:10.1038/s41586-026-10330-z
Identification of genetic variants associated with the efficacy and side effects of GLP1 medications could underpin development of precision medicine approaches in the treatment of obesity.Stabilizing Rubric Integration Training via Decoupled Advantage Normalization
Targeting the OXNAD1-PTGS2 axis with resveratrol overcomes ferroptosis Inhibition and reverses 5-FU resistance in gastric cancer
Gastric Cancer. 2026 Mar 13. doi: 10.1007/s10120-026-01718-x. Online ahead of print.
ABSTRACT
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.
PMID:41824193 | DOI:10.1007/s10120-026-01718-x