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Targeting UXS1-Dependent Glucuronate Detoxification Potentiates Metformin's Anti-Tumor Efficacy in Lung

Qihai Sui1,2,3, Zhencong Chen1, Guangyao Shan1

  • 1Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|May 10, 2026
PubMed

Insights

Metformin alters glucuronic acid metabolism in lung cancer by activating UGDH, increasing reliance on UXS1. Targeting UXS1 with plantainoside enhances metformin

Area of Science:

  • Oncology
  • Metabolomics
  • Cancer Metabolism

Background:

  • Metformin shows experimental anti-tumor effects but yields contradictory clinical results.
  • Understanding metformin's complex role in cancer is crucial for therapeutic development.

Purpose of the Study:

  • To elucidate metformin's novel mechanism in lung adenocarcinoma (LUAD) through metabolomics.
  • To identify new therapeutic strategies combining metformin with targeted agents.

Main Methods:

  • Metabolomics analysis of LUAD samples, xenografts, and cells.
  • Investigated metformin's effect on glucuronic acid metabolism and UGDH phosphorylation.
  • Virtual screening identified UXS1 inhibitors, with plantainoside selected for further study.

Main Results:

  • Metformin promotes UDP-glucose to UDP-glucuronic acid conversion by activating UGDH(S476), increasing cell dependence on UXS1.
  • Plantainoside, a UXS1 inhibitor, synergizes with metformin to induce lethal effects in LUAD models.
  • The combination enhances immunotherapy by boosting CD8+ T cells and suppressing macrophage differentiation.

Conclusions:

  • Metformin's action involves a novel pathway in glucuronic acid metabolism and UXS1 dependence.
  • Targeting UXS1 in combination with metformin presents a promising new strategy for LUAD treatment and immunotherapy enhancement.
Keywords:
UGDHUXS1glucuronic acid metabolismlung cancermetformin

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