Discovery of 12-O-deacetyl-phomoxanthone a as a novel blocker of P2X7R/NLRP3 inflammasome for treating intestinal and vascular inflammation

The P2X7R/NLRP3 inflammasome axis plays a critical role in the pathogenesis of ulcerative colitis (UC) and sepsis. We previously demonstrated 12-O-deacetyl-phomoxanthone A (12-ODPXA), a representative xanthone dimer extracted from fungi, exhibit an effective anti-tumor property; however, it is totally unknown whether 12-ODPXA has any effects against UC and sepsis; and if so, whether it exerts anti-inflammatory effects by blocking P2X7R/NLRP3 inflammasome. In the present study, we first observed that 12-ODPXA significantly inhibited Pyroptosis and the expression of inflammatory factors in both LPS/ATP-stimulated immortalized bone marrow-derived macrophages (iBMDMs) and peritoneal macrophages (PMs), and attenuated inflammatory response in intestinal epithelial cells (IECs). 12-ODPXA targeted P2X7R and NLRP3 to suppress the activation of NLRP3 inflammasome via P2X7R/CA²⁺ and NF-κB signaling pathways. 12-ODPXA also significantly ameliorated UC and sepsis. Moreover, 12-ODPXA dose-dependently induced vasorelaxation of mesenteric arterioles predominantly via EDH mechanism, and rescued the impaired ACh/EDH-mediated vasorelaxation in sepsis. Overall, this study highlights the efficacy of 12-ODPXA against intestinal and vascular inflammation in mice through inhibition of the P2X7R/NLRP3 inflammasome pathway, identifying 12-ODPXA as a promissing therapeutic candidate for UC and sepsis.