Objective To investigate the mechanism of fisetin inhibiting the activation of microglia NOD-like receptor family protein 3(NLRP3)inflammasome in microglia and alleviating cognitive impairment after sepsis.Methods C57BL/6 mice were used to establish the sepsis model by cecal ligation and puncture.Mice were divided into four groups:the sham group,the sepsis group,the sepsis+caspase-1 knockout group(sepsis+Cas-1-/-group)and the sepsis+fisetin group.Evans blue was used to detect the permeability of blood-brain barrier(BBB).Morris water maze was used to evaluate the cognitive function of mice.Western blot assay and immunofluorescence double staining were used to detect the expression of NLRP3 inflammasome-related proteins including caspase-1,N-terminal fragment of the GSDMD(GSDMD-N),interleukin(IL)-1β,IL-18 and mitophagy-related proteins(Pink1,Parkin and LC3-Ⅱ)in brain tissue and microglia.Results Compared with the sham group,expression levels of caspase-1,GSDMD-N,IL-1β and IL-18 were significantly increased in the sepsis group(P＜0.05).Compared with the sepsis group,expression levels of caspase-1,GSDMD-N,IL-1β and IL-18 were significantly decreased in the sepsis+Cas-1-/-group(P＜0.05).The expression levels of Pink1,Parkin and LC3-Ⅱ were significantly higher in the sepsis+fisetin group than those of the sepsis group(P＜0.05),and expression levels of caspase-1,GSDMD-N,IL-1β and IL-18 were significantly lower(P＜0.05).After fisetin intervention,the permeability of BBB was decreased and the cognitive impairment(decreased escape latency and increased frequencies of crossing the platform)was alleviated in the sepsis+fisetin group compared with those of the sepsis group(P＜0.05).Conclusion Fisetin may alleviate central inflammation and cognitive impairment after sepsis by inhibiting the activation of microglial NLRP3 inflammasome through activating mitophagy.