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S1PR1-biased activation drives the resolution of endothelial dysfunction-associated inflammatory diseases by maintaining endothelial integrity

Author

Listed:
  • Huaping Zheng

    (Sichuan University)

  • Jingjing Yu

    (Sichuan University
    Sichuan University)

  • Luhua Gao

    (Sichuan University)

  • Kexin Wang

    (Sichuan University
    Sichuan University)

  • Zheng Xu

    (Sichuan University)

  • Zhen Zeng

    (Sichuan University)

  • Kun Zheng

    (Sichuan University)

  • Xiaoju Tang

    (Sichuan University)

  • Xiaowen Tian

    (Sichuan University
    Sichuan University)

  • Qing Zhao

    (Sichuan University)

  • Jie Zhao

    (Tianfu Jincheng Laboratory)

  • Huajing Wan

    (Sichuan University)

  • Zhongwei Cao

    (Sichuan University)

  • Kang Zhang

    (Macau University of Science and Technology and University Hospital)

  • Jingqiu Cheng

    (Sichuan University)

  • Jürgen Brosius

    (Sichuan University)

  • Hu Zhang

    (Sichuan University)

  • Wei Li

    (Sichuan University)

  • Wei Yan

    (Sichuan University
    Tianfu Jincheng Laboratory)

  • Zhenhua Shao

    (Sichuan University
    Sichuan University
    Tianfu Jincheng Laboratory)

  • Fengming Luo

    (Sichuan University)

  • Cheng Deng

    (Sichuan University)

Abstract

G protein-coupled sphingosine-1-phosphate receptor 1 (S1PR1), a drug target for inflammatory bowel disease (IBD), enables immune cells to egress from lymph nodes, but the treatment increases the risk of immunosuppression. The functional signaling pathway triggered by S1PR1 activation in endothelial cells and its therapeutic application remains unclear. Here, we showed that S1PR1 is highly expressed in endothelial cells of IBD patients and positively correlated with endothelial markers. Gi-biased agonist-SAR247799 activated S1PR1 and reversed pathology in male mouse and organoid IBD models by protecting the integrity of the endothelial barrier without affecting immune cell egress. Cryo-electron microscopy structure of S1PR1-Gi signaling complex bound to SAR247799 with a resolution of 3.47 Å revealed the recognition mode for the biased ligand. With the efficacy of SAR247799 in treating other endothelial dysfunction-associated inflammatory diseases, our study offers mechanistic insights into the Gi-biased S1PR1 agonist and represents a strategy for endothelial dysfunction-associated disease treatment.

Suggested Citation

  • Huaping Zheng & Jingjing Yu & Luhua Gao & Kexin Wang & Zheng Xu & Zhen Zeng & Kun Zheng & Xiaoju Tang & Xiaowen Tian & Qing Zhao & Jie Zhao & Huajing Wan & Zhongwei Cao & Kang Zhang & Jingqiu Cheng & , 2025. "S1PR1-biased activation drives the resolution of endothelial dysfunction-associated inflammatory diseases by maintaining endothelial integrity," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57124-x
    DOI: 10.1038/s41467-025-57124-x
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