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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
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    References listed on IDEAS

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    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.
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