Role of IFIT3-mediated mitochondrial reactive oxygen species pathway in acute synaptic injury during sepsis
Han Xiaoman
Zhou You
Lei Yiming
Du Jiamin
Li Jing
Luo Ziqian
Cheng Li
Yan Juanjuan
Wei Jie
Zhou Chenliang
Abstract：Objective To elucidate the key molecules and underlying mechanisms of hippocampal synaptic injury during the acute stage(6 hours after onset)of sepsis-associated encephalopathy(SAE)and the early neuronal injury pathway in sepsis-induced cognitive impairment(SICI).Methods Proteomic screening was performed in mouse hippocampal tissues 6 hours post-lipopolysaccharide(LPS)administration to determine candidate targets.An HT22 neuronal cell line with overexpression of interferon-induced protein with tetratricopeptide repeats 3(IFIT3)was established in vitro.Cells were divided into 6 groups:control,LPS,IFIT3 overexpression,LPS+IFIT3,Visomitin pretreatment,and CY-09 cotreatment.The levels of mitochondrial reactive oxygen species(mtROS),IL-1β release,and the expression of postsynaptic density protein 95(PSD95)and synaptophysin(SYN)were detected.Results IFIT3 expression was significantly up-regulated in hippocampus 6 hours after LPS exposure.Under inflammatory conditions,IFIT3 overexpression exacerbated mtROS accumulation,increased IL-1β release,and reduced PSD95 and SYN.Upstream clearance of mtROS by Visomitin markedly inhibited synaptic protein loss,showing a superior protective effect compared with the NOD-like receptor family pyrin domain containing 3(NLRP3)inflammasome inhibitor CY-09.Conclusions IFIT3 aggravates acute hippocampal synaptic injury during sepsis,a process closely linked to the activation of the mtROS-NLRP3 inflammasome cascade.These results indicate that early upstream targeting of mtROS may be more effective than isolated inhibition of NLRP3,providing experimental evidence for precise intervention against acute cognitive impairment in sepsis.
Keywords：SepsisInterferon-induced protein with tetratricopeptide repeats 3Mitochondrial reactive oxygen speciesInflammasomeSynaptic injury
Publication Date：2026-02-10
Online Publishing Date：2026-03-18(First online date of this platform, not the publication date of the document)
Pages：8( 92-99 )