Objective To explore the role of protective function of Sestrin2(Sesn2)to mitochondria in alleviating cognitive dysfunction in mice with sepsis-associated encephalopathy(SAE).Methods 6-week-old male C57BL/6J mice were randomly divided into three groups:sham group,CLP group and CLP plus eupatilin group,40 mice in each group.A sepsis model was induced by cecal ligation and perforation(CLP).The CLP plus eupatilin group was treated with eupatilin.Neurobehavioral test and Morris water maze(MWM)were used to deter-mine neurobehavior and spatial learning and memory function in mice.The number of neurons in hippocampal CA1 area was counted by Nissl staining.HT22 cells were randomly divided into a control group(Con),lipopolysaccha-ride group(LPS),LPS plus eupatilin treatment group(LPS plus eupatilin)and LPS plus eupatilin and Nrf2 siRNA treatment group(LPS plus eupatilin and si-Nrf2).Apoptosis was analyzed by terminal deoxynucleotidyl transferase-mediated nick end labeling(TUNEL)staining,Mitochondrial membrane potential(MMP)was used to analyze mitochondrial damage.Results Seven days after CLP,as compared with sham mice,Sesn2 in hippocampus and cortex decreased significantly in CLP mice(P<0.01).As compared with CLP group,the survival rate in CLP plus eupatilin group increased significantly(P<0.05).As compared with sham group,the mice in CLP group showed a relatively high nerve injury score(P<0.05),and had fewer platform crossings and shorter target stay time,while the mice in CLP plus eupatilin group exhibited a lower injury score(P<0.05),and stayed in the target area for a longer time(P<0.05).As compared with sham group,the co-localization rate of neurons,Sesn2 and Nrf2 in CLP group decreased significantly(P<0.05),and the number of CD68/Iba-1 positive microglia increased significantly(P<0.05),while CLP plus eupatilin group reversed these changes.As compared with Con group,apoptosis and MMP level in LPS group increased significantly(P<0.01),while apoptosis and MMP level in LPS plus eupatilin group were lower than those in LPS group(P<0.05).However,Nrf2 knockdown(LPS plus eupatilin and si-Nrf2 group)reversed the anti-apoptosis and mitochondrial protection of eupatilin.Conclusions Eupatilin can alleviate cognitive dysfunction and neurological deficit in SAE mice by activating Sesn2-Nrf2 pathway,and improve inflammatory microenvironment by alleviating mitochondrial dysfunction.