Inhibition of the P2X7/NLRP3 Inflammasome Signaling Pathway by Deacetylgedunin from Toona sinensis

Limonoids are considered the effective part in Meliaceae plants that exert anti-inflammatory effects. Gedunin-type limonoids specifically have anti-inflammatory effects. However, the role of gedunin-type limonoids in the inflammatory diseases mediated by NLRP3 inflammasome remains to be explored. We found that deacetylgudunin (DAG), a gedunin-type limonoid from Toona sinensis, had similar anti-inflammatory effects and lower toxicity than gedunin. Further studies showed that DAG down-regulated the NF-κB pathway, inhibited K⁺ efflux and ROS release, inhibited ASC oligomerization, and significantly weakened the interaction of NLRP3 with ASC and NEK7. Furthermore, DAG could not further inhibit IL-1β secretion and K⁺ efflux when combined with the P2X7 inhibitor A438079. In conclusion, our research revealed that DAG exerted an anti-inflammatory effect by inhibiting the P2X7/NLRP3 signaling pathway and enriched the application of gedunin-type limonoids in inflammatory diseases driven by the NLRP3 inflammasome.