Objective To explore the ameliorative effect of astragaloside Ⅳ on depression induced by chronic social defeat stress (CSDS). Methods (1) C57BL/6J mice were randomly divided into control group, model group, or astragaloside Ⅳ low⁃, medium⁃, and high⁃dose groups, or positive drug group, with 8 mice in each group. CD⁃1 retired breeder mice were used to attack the C57BL/6J mice continuously for 10 days to establish the CSDS⁃induced depression model. Simultaneously, 30 minutes before modeling, the astragaloside Ⅳ low⁃, medium⁃, and high⁃dose groups received intragastric administration of astragaloside Ⅳ in 10 mg/kg, 20 mg/kg, and 40 mg/kg, respectively. The positive drug group received intragastric administration of 10 mg/kg fluoxetine, and the model group of distilled water, whereas the control group received no intervention and was normally fed. Behavioral tests were conducted using the forced swim test and elevated plus maze test. (2) The effect targets of astragaloside Ⅳ were screened using the GeneCards®, SwissTargetPrediction, PharmMapper, and SuperPred databases, while depression⁃related targets were screened using the GeneCards®, OMIM®, and DisGeNET databases. The intersection targets between the two sets were identified, and a protein⁃protein interaction (PPI) network was constructed according to the intersection targets to screen core targets. Gene Ontology functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed. Finally, a “drug⁃target⁃pathway⁃disease” network was constructed. Results (1) Compared with the control group, the model group exhibited increased immobility time, along with decreased proportions of open arm entry and of open arm time (P<0.05). In contrast, astragaloside Ⅳ in various doses groups and the positive drug group exhibited reduced immobility time and increased proportions of open arm entry and of open arm time compared to the model group (P<0.05). (2) A total of 192 intersection targets were identified between astragaloside Ⅳ's effect targets and depression⁃related targets. PPI network analysis revealed that core targets for astragaloside Ⅳ's antidepressant effects included Src tyrosine kinase, interleukin 6, protein kinase B, and interleukin 1β. Enrichment analysis demonstrated that these intersection targets were primarily enriched in cellular components such as plasma membrane, receptor complex, dendrites, and glutamatergic synapses, in biological processes such as response to xenobiotic stimulus, positive regulation of extracellular regulated protein kinase (ERK)1 and ERK2 cascade, and signal transduction, in molecular functions such as nuclear receptor activity, enzyme binding, and identical protein binding, and in signaling pathways such as signaling pathways in cancer, advanced glycation end products⁃receptor for advanced glycation end products signaling pathway, hypoxia⁃inducible 1 signaling pathway, and cyclic adenosine monophosphate signaling pathway. Conclusion Astragaloside Ⅳ can treat CSDS⁃induced depression through multi⁃target and multi⁃pathway synergistic action.

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