Figure 8

Schematic representation of the inhibitory effect of fisetin on the NLRP3 inflammasome in BV2 microglial cells. Fisetin inhibits the formation of the NLRP3 inflammasome primarily via two signaling pathways. In the first signaling pathway, fisetin competitively antagonizes the recognition of LPS by the TLR4/MD2 complex by binding to SER438 of TLR4 and occluding the hydrophobic pocket of MD2. This inhibits the canonical NF-κB signaling pathway, which consequently suppresses the transcription of IL-1β. In the second pathway, fisetin downregulates the production of mtROS by promoting the elimination of damaged mitochondria in a p62-dependent manner. The inhibition of mtROS production is associated with a decrease in the formation of the NLRP3 inflammasome, which subsequently inhibits the caspase-1-mediated cleavage of pro-IL-1β to active IL-1β. P2RX7, P2X purinoceptor 7.