IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-57124-x.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-57124-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-57124-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Tuoyi Li & Bing Yu & Zhixin Liu & Jingyuan Li & Mingliang Ma & Yingbao Wang & Mingjiang Zhu & Huiyong Yin & Xiaofeng Wang & Yi Fu & Fang Yu & Xian Wang & Xiaohong Fang & Jinpeng Sun & Wei Kong, 2018. "Homocysteine directly interacts and activates the angiotensin II type I receptor to aggravate vascular injury," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    2. Zheng Xu & Lulu Guo & Jingjing Yu & Siyuan Shen & Chao Wu & Weifeng Zhang & Chang Zhao & Yue Deng & Xiaowen Tian & Yuying Feng & Hanlin Hou & Lantian Su & Hongshuang Wang & Shuo Guo & Heli Wang & Kexi, 2023. "Ligand recognition and G-protein coupling of trace amine receptor TAAR1," Nature, Nature, vol. 624(7992), pages 672-681, December.
    3. Mehrdad Matloubian & Charles G. Lo & Guy Cinamon & Matthew J. Lesneski & Ying Xu & Volker Brinkmann & Maria L. Allende & Richard L. Proia & Jason G. Cyster, 2004. "Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1," Nature, Nature, vol. 427(6972), pages 355-360, January.
    4. Fan Yang & Chunyou Mao & Lulu Guo & Jingyu Lin & Qianqian Ming & Peng Xiao & Xiang Wu & Qingya Shen & Shimeng Guo & Dan-Dan Shen & Ruirui Lu & Linqi Zhang & Shenming Huang & Yuqi Ping & Chenlu Zhang &, 2020. "Structural basis of GPBAR activation and bile acid recognition," Nature, Nature, vol. 587(7834), pages 499-504, November.
    5. Eric Bender, 2017. "Cancer immunotherapy," Nature, Nature, vol. 552(7685), pages 61-61, December.
    6. Jie Zhao & Hong Fu & Jingjing Yu & Weiqi Hong & Xiaowen Tian & Jieyu Qi & Suyue Sun & Chang Zhao & Chao Wu & Zheng Xu & Lin Cheng & Renjie Chai & Wei Yan & Xiawei Wei & Zhenhua Shao, 2023. "Prospect of acromegaly therapy: molecular mechanism of clinical drugs octreotide and paltusotine," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    7. Hiroaki Akasaka & Tatsuki Tanaka & Fumiya K. Sano & Yuma Matsuzaki & Wataru Shihoya & Osamu Nureki, 2022. "Structure of the active Gi-coupled human lysophosphatidic acid receptor 1 complexed with a potent agonist," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    8. Chun-Hua Liu & Zheng Gong & Zong-Lai Liang & Zhi-Xin Liu & Fan Yang & Yu-Jing Sun & Ming-Liang Ma & Yi-Jing Wang & Chao-Ran Ji & Yu-Hong Wang & Mei-Jie Wang & Fu-Ai Cui & Amy Lin & Wen-Shuai Zheng & D, 2017. "Arrestin-biased AT1R agonism induces acute catecholamine secretion through TRPC3 coupling," Nature Communications, Nature, vol. 8(1), pages 1-17, April.
    9. Shian Liu & Navid Paknejad & Lan Zhu & Yasuyuki Kihara & Manisha Ray & Jerold Chun & Wei Liu & Richard K. Hite & Xin-Yun Huang, 2022. "Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Tamaki Izume & Ryo Kawahara & Akiharu Uwamizu & Luying Chen & Shun Yaginuma & Jumpei Omi & Hiroki Kawana & Fengjue Hou & Fumiya K. Sano & Tatsuki Tanaka & Kazuhiro Kobayashi & Hiroyuki H. Okamoto & Yo, 2024. "Structural basis for lysophosphatidylserine recognition by GPR34," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Xuan Zhang & Yujing Wang & Shreyas Supekar & Xu Cao & Jingkai Zhou & Jessica Dang & Siqi Chen & Laura Jenkins & Sara Marsango & Xiu Li & Guibing Liu & Graeme Milligan & Mingye Feng & Hao Fan & Weimin , 2023. "Pro-phagocytic function and structural basis of GPR84 signaling," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Yiyi Zhang & Sidan Tian & Liping Huang & Yanan Li & Yuan Lu & Hongyu Li & Guiping Chen & Fanling Meng & Gang L. Liu & Xiangliang Yang & Jiasheng Tu & Chunmeng Sun & Liang Luo, 2022. "Reactive oxygen species-responsive and Raman-traceable hydrogel combining photodynamic and immune therapy for postsurgical cancer treatment," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Kateryna Onyshchenko & Ren Luo & Elena Guffart & Simone Gaedicke & Anca-Ligia Grosu & Elke Firat & Gabriele Niedermann, 2023. "Expansion of circulating stem-like CD8+ T cells by adding CD122-directed IL-2 complexes to radiation and anti-PD1 therapies in mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. Aika Iwama & Ryoji Kise & Hiroaki Akasaka & Fumiya K. Sano & Hidetaka S. Oshima & Asuka Inoue & Wataru Shihoya & Osamu Nureki, 2024. "Structure and dynamics of the pyroglutamylated RF-amide peptide QRFP receptor GPR103," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    6. Xin Chen & Kexin Wang & Jianfang Chen & Chao Wu & Jun Mao & Yuanpeng Song & Yijing Liu & Zhenhua Shao & Xuemei Pu, 2024. "Integrative residue-intuitive machine learning and MD Approach to Unveil Allosteric Site and Mechanism for β2AR," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    7. Carolina V Messias & Eliane Santana-Van-Vliet & Julia P Lemos & Otacilio C Moreira & Vinicius Cotta-de-Almeida & Wilson Savino & Daniella Arêas Mendes-da-Cruz, 2016. "Sphingosine-1-Phosphate Induces Dose-Dependent Chemotaxis or Fugetaxis of T-ALL Blasts through S1P1 Activation," PLOS ONE, Public Library of Science, vol. 11(1), pages 1-20, January.
    8. Jie Cai & Jie Peng & Juan Feng & Ruocheng Li & Peng Ren & Xinwei Zang & Zezong Wu & Yi Lu & Lin Luo & Zhenzhen Hu & Jiaying Wang & Xiaomeng Dai & Peng Zhao & Juan Wang & Mi Yan & Jianxin Liu & Renren , 2023. "Antioxidant hepatic lipid metabolism can be promoted by orally administered inorganic nanoparticles," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    9. Geng Chen & Jun Xu & Asuka Inoue & Maximilian F. Schmidt & Chen Bai & Qiuyuan Lu & Peter Gmeiner & Zheng Liu & Yang Du, 2022. "Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    10. Wessel A. C. Burger & Vi Pham & Ziva Vuckovic & Alexander S. Powers & Jesse I. Mobbs & Yianni Laloudakis & Alisa Glukhova & Denise Wootten & Andrew B. Tobin & Patrick M. Sexton & Steven M. Paul & Chri, 2023. "Xanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChR," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    11. Minfei Su & Jinan Wang & Guoqing Xiang & Hung Nguyen Do & Joshua Levitz & Yinglong Miao & Xin-Yun Huang, 2023. "Structural basis of agonist specificity of α1A-adrenergic receptor," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    12. Jiale Liang & Asuka Inoue & Tatsuya Ikuta & Ruixue Xia & Na Wang & Kouki Kawakami & Zhenmei Xu & Yu Qian & Xinyan Zhu & Anqi Zhang & Changyou Guo & Zhiwei Huang & Yuanzheng He, 2023. "Structural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    13. Huanyu Z. Li & Ashley C. W. Pike & Yung-Ning Chang & Dheeraj Prakaash & Zuzana Gelova & Josefina Stanka & Christophe Moreau & Hannah C. Scott & Frank Wunder & Gernot Wolf & Andreea Scacioc & Gavin McK, 2025. "Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    14. Lin Cheng & Zhuang Miao & Sicen Liu & Zhe Li & Hong Fu & Chanjuan Xu & Shilong Hu & Chang Zhao & Yuxuan Liu & Tiantian Zhao & Wencheng Liu & Heli Wang & Runduo Liu & Wei Yan & Xiangdong Tang & Jianfen, 2024. "Cryo-EM structure of small-molecule agonist bound delta opioid receptor-Gi complex enables discovery of biased compound," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    15. Hiroaki Akasaka & Tatsuki Tanaka & Fumiya K. Sano & Yuma Matsuzaki & Wataru Shihoya & Osamu Nureki, 2022. "Structure of the active Gi-coupled human lysophosphatidic acid receptor 1 complexed with a potent agonist," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    16. Navid Paknejad & Vinay Sapuru & Richard K. Hite, 2023. "Structural titration reveals Ca2+-dependent conformational landscape of the IP3 receptor," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    17. João Pedro Pereira & Jason G Cyster & Ying Xu, 2010. "A Role for S1P and S1P1 in Immature-B Cell Egress from Mouse Bone Marrow," PLOS ONE, Public Library of Science, vol. 5(2), pages 1-6, February.
    18. Maria Pino & Amélie Pagliuzza & M. Betina Pampena & Claire Deleage & Elise G. Viox & Kevin Nguyen & Inbo Shim & Adam Zhang & Justin L. Harper & Sadia Samer & Colin T. King & Barbara Cervasi & Kiran P., 2022. "Limited impact of fingolimod treatment during the initial weeks of ART in SIV-infected rhesus macaques," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57124-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.