Exploring The Mechanism Of Action Of 4-octyl Itaconate Against Sepsis Based On Network Pharmacology

Research Background and Purpose:Sepsis remains one of the leading life-threatening health threats worldwide,associated with approximately 20% of deaths each year.Although the pathophysiological mechanism and treatment of sepsis have been studied extensively in the past few decades,the management of sepsis is still focused on symptomatic treatment.Previous studies have shown that 4-Octyl itaconate(4-OI)can improve the survival rate of mice with sepsis,but the exact mechanism of action is unclear,which limits the development of 4-OI drugs and increases the time cost of clinical application and development.In this study,the key genes,biological functions and signaling pathways of 4-OI treatment for sepsis were further explored by combining the bio-computer technology,network pharmacology and molecular docking technology.Materials and methods:We from the GeneCards pool and the gene expression(Gene Expression Omnibus,GEO)extract pathological targets of sepsis.Likewise,through Swiss Target Prediction(STP),Similarity ensemble approach(SEA),and 4-OI Target Net database access of pharmacological targets.Next,all potential targets for 4-OI anti-sepsis were initially screened using an online platform Draw Venn diagram.Then,core genes were screened using the Cytohubba analysis tool in Cytoscape software.GO and KEGG enrichment analysis and protein interaction network(PPI)analysis related to core genes were conducted using online analysis software.In addition,the validation set analyzed the diagnostic ability of core genes in sepsis and the differential expression of multiple organ dysfunction in sepsis.The reliability of the prediction of core genes was verified by molecular docking technology,and the key genes and mechanism of action of4-OI in the treatment of sepsis were revealed.Results:After target screening for 4-OI and sepsis,264 pharmacological targets and1953 pathological targets were obtained,as well as 72 genes related to 4-OI anti-sepsis,and 8 core genes were screened out,which were MMP9,MMP2,SIRT1,PPARA,PTPRC,NOS3,TLR2,HSP90AA1.The GO and KEGG pathway analysis of 8 core genes indicated that they may be related to the regulation of nitric oxide synthase activity,macrophage differentiation,positive regulation of protein phosphorylation,neutrophil granulocyte granulation response,response to hypoxia,IL-17 signaling pathway,PI3K-Akt signaling pathway,and on proteoglycans.The validation data set showed that 8 core genes were significantly differentially expressed in sepsis and non-sepsis groups,MMP9 was significantly differentially expressed in the sepsis survival group and non-survival group,and HSP90AA1,MMP2,PTPRC,PPARA,and MMP9 had high diagnostic ability in the diagnosis of sepsis.Molecular docking results showed that the molecular docking scores of 8 core genes with 4-octyl itaconate were all less than0kcal/mol,and 4-OI was well combined with the core target of sepsis.Conclusion:4-OI plays an anti-sepsis role by regulating MMP9,MMP2,SIRT1,PPARA,PTPRC,NOS3,TLR2,and HSP90AA1,and plays an important role in the diagnosis of multiple organ damage in sepsis.MMP9 may be a reliable gene for the prognosis and diagnosis of sepsis.These core genes may provide new insights into subsequent5-4-OI treatment targets for sepsis.