Purinergic signaling plays a causal role in the pathogenesis of inflammatory bowel disease. Among purinoceptors, only P2Y 14R is positively correlated with inflammatory score in mucosal biopsies of ulcerative colitis patients, nevertheless, the role of P2Y 14R in ulcerative colitis remains unclear. Here, based on the over-expressions of P2Y 14R in the intestinal epithelium of mice with experimental colitis, we find that male mice lacking P2Y 14R in intestinal epithelial cells exhibit less intestinal injury induced by dextran sulfate sodium. Mechanistically, P2Y 14R 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 P2Y 14R antagonist HDL-16, which exhibits remarkable anti-colitis effects. Summarily, our study elucidates a previously unknown mechanism whereby P2Y 14R participates in ulcerative colitis, providing a promising therapeutic target for inflammatory bowel disease.
P2Y 14R regulates necroptosis of intestinal epithelial cells though PKA/CREB/RIPK1 axis in the pathogenesis of ulcerative colitis (UC). Targeting P2Y 14R with a small molecule inhibitor improves dextran sulfate sodium-induced UC in mice, suggesting P2Y 14R as a promising target for treatment of UC.