Targeting P2YR protects against necroptosis of intestinal epithelial cells through PKA/CREB/RIPK1 axis in ulcerative colitis.

Purinergic signaling plays a causal role in the pathogenesis of inflammatory bowel disease. Among purinoceptors, only P2YR is positively correlated with inflammatory score in mucosal biopsies of ulcerative colitis patients, nevertheless, the role of P2YR in ulcerative colitis remains unclear. Here, based on the over-expressions of P2YR in the intestinal epithelium of mice with experimental colitis, we find that male mice lacking P2YR in intestinal epithelial cells exhibit less intestinal injury induced by dextran sulfate sodium. Mechanistically, P2YR 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 P2YR antagonist HDL-16, which exhibits remarkable anti-colitis effects. Summarily, our study elucidates a previously unknown mechanism whereby P2YR participates in ulcerative colitis, providing a promising therapeutic target for inflammatory bowel disease.