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

Chunxiao Liu, Hui Wang, Lu Han, Yifan Zhu, Shurui Ni, Jingke Zhi, Xiping Yang, Jiayi Zhi, Tian Sheng, Huanqiu Li () and Qinghua Hu ()
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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

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46365-x

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