IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-46365-x.html
   My bibliography  Save this article

Targeting P2Y14R protects against necroptosis of intestinal epithelial cells through PKA/CREB/RIPK1 axis in ulcerative colitis

Author

Listed:
  • Chunxiao Liu

    (China Pharmaceutical University)

  • Hui Wang

    (Soochow University)

  • Lu Han

    (China Pharmaceutical University)

  • Yifan Zhu

    (Soochow University)

  • Shurui Ni

    (China Pharmaceutical University)

  • Jingke Zhi

    (China Pharmaceutical University)

  • Xiping Yang

    (China Pharmaceutical University)

  • Jiayi Zhi

    (China Pharmaceutical University)

  • Tian Sheng

    (Soochow University)

  • Huanqiu Li

    (Soochow University)

  • Qinghua Hu

    (China Pharmaceutical University)

Abstract

Purinergic signaling plays a causal role in the pathogenesis of inflammatory bowel disease. Among purinoceptors, only P2Y14R is positively correlated with inflammatory score in mucosal biopsies of ulcerative colitis patients, nevertheless, the role of P2Y14R in ulcerative colitis remains unclear. Here, based on the over-expressions of P2Y14R in the intestinal epithelium of mice with experimental colitis, we find that male mice lacking P2Y14R in intestinal epithelial cells exhibit less intestinal injury induced by dextran sulfate sodium. Mechanistically, P2Y14R deletion limits the transcriptional activity of cAMP-response element binding protein through cAMP/PKA axis, which binds to the promoter of Ripk1, inhibiting necroptosis of intestinal epithelial cells. Furthermore, we design a hierarchical strategy combining virtual screening and chemical optimization to develop a P2Y14R antagonist HDL-16, which exhibits remarkable anti-colitis effects. Summarily, our study elucidates a previously unknown mechanism whereby P2Y14R participates in ulcerative colitis, providing a promising therapeutic target for inflammatory bowel disease.

Suggested Citation

  • Chunxiao Liu & Hui Wang & Lu Han & Yifan Zhu & Shurui Ni & Jingke Zhi & Xiping Yang & Jiayi Zhi & Tian Sheng & Huanqiu Li & Qinghua Hu, 2024. "Targeting P2Y14R protects against necroptosis of intestinal epithelial cells through PKA/CREB/RIPK1 axis in ulcerative colitis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46365-x
    DOI: 10.1038/s41467-024-46365-x
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-46365-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-46365-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. Jingwei Ma & Keke Wei & Junwei Liu & Ke Tang & Huafeng Zhang & Liyan Zhu & Jie Chen & Fei Li & Pingwei Xu & Jie Chen & Jincheng Liu & Haiqing Fang & Liang Tang & Dianheng Wang & Liping Zeng & Weiwei S, 2020. "Glycogen metabolism regulates macrophage-mediated acute inflammatory responses," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    2. Patrick-Simon Welz & Andy Wullaert & Katerina Vlantis & Vangelis Kondylis & Vanesa Fernández-Majada & Maria Ermolaeva & Petra Kirsch & Anja Sterner-Kock & Geert van Loo & Manolis Pasparakis, 2011. "FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation," Nature, Nature, vol. 477(7364), pages 330-334, September.
    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. Xiaoke Yang & Mingqi Zhu & Xue Lu & Yuxin Wang & Junyu Xiao, 2024. "Architecture and activation of human muscle phosphorylase kinase," Nature Communications, Nature, vol. 15(1), pages 1-14, 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:15:y:2024:i:1:d:10.1038_s41467-024-46365-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.