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

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, Jürgen Brosius, Hu Zhang, Wei Li, Wei Yan (), Zhenhua Shao (), Fengming Luo () and Cheng Deng ()
Additional contact information
Huaping Zheng: Sichuan University
Jingjing Yu: Sichuan University
Luhua Gao: Sichuan University
Kexin Wang: Sichuan University
Zheng Xu: Sichuan University
Zhen Zeng: Sichuan University
Kun Zheng: Sichuan University
Xiaoju Tang: Sichuan University
Xiaowen Tian: 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
Zhenhua Shao: Sichuan University
Fengming Luo: Sichuan University
Cheng Deng: Sichuan University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57124-x

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