基于网络药理学和血清代谢组学探讨洋川芎内酯Ⅰ改善脓毒症急性肝损伤作用机制OA

Objective:To investigate the mechanism of senkyunolide I in ameliorating sepsis-associated acute liver injury.Methods:Network pharmacology was employed to screen the targets of senkyunolide I in treating sepsis-associat-ed liver injury.The Venn diagram was constructed to obtain common targets for the construction of the protein-protein in-teraction(PPI)network.The core targets screened out were subjected to GO and KEGG pathway enrichment analyses and molecular docking.A rat model of lipopolysaccharide(LPS)-induced sepsis was established.Differential metabo-lites were detected by non-targeted serum metabolomics,and associated metabolic pathways were enriched.Rats were treated with senkyunolide I via intraperitoneal injection,and the therapeutic effects on LPS-induced sepsis in rats were e-valuated.The serum levels of biomedical indicators,inflammatory cytokines,and oxidative stress markers were quanti-fied.Hepatic histopathology was assessed through hematoxylin-eosin(HE)staining.Western blot was employed to de-termine the protein levels of peroxisome proliferator-activated receptor alpha(PPAR-α)and glutathione peroxidase 4(GPX4)in the liver tissue.Results:Network pharmacology predicted that the core targets of senkyunolide I for treating sepsis-associated acute liver injury were EGFR,AKT1,SRC,JUN,MMP9,and PPARG,involving IL-17,TNF,PI3K-AKT,PPAR,and NF-κB signaling pathways.Metabolomic analysis revealed 24 differential metabolites between the mod-el group and the senkyunolide I group.These differential metabolites were mainly associated with metabolic pathways in-cluding lysine degradation,PPAR signaling,phosphorylation of pentose,linoleic acid metabolism,biosynthesis of pantetic acid and coenzyme A,type C agglutinin receptor,and fatty acid metabolism.Animal experiment results showed that com-pared with the model group,senkyunolide I intervention reduced the serum levels of ALT,interleukin(IL)-1β,IL-6,and malondiadehyde(MDA)(P<0.05,P<0.01),increased the superoxide dismutase(SOD)and glutathione(GSH)activ-ities(P<0.05,P<0.01),and up-regulated the protein levels of PPAR-α and GPX4(P<0.05,P<0.01).Furthermore,senkyunolide I reduced the pathological changes including inflammatory infiltration,hepatocellular necrosis,and bile can-aliculus hyperplasia.Conclusion:Senkyunolide I can ameliorate sepsis-associated acute liver injury by inhibiting inflam-mation and oxidative stress response,which may be related to regulation of the PPAR-α/GPX4 signaling pathway.