Objective: Acanthopanax senticosus (Rupr. et Maxim.) Harms (ASH) is a traditional herbal medicine widely known for its antifatigue and antistress effects, as well as tonifying qi, invigorating spleen and kidney, and tranquilizing the mind. Recent evidence suggests that ASH has a therapeutic effect on major depressive disorder (MDD), but its mechanism is still unclear. The current study aimed to investigate the effect of ASH on MDD and potential therapeutic mechanisms. Materials and Methods: The chemical compound potential target network was predicted based on network pharmacology. Simultaneously, chronic unpredictable mild stress (CUMS) model mice were orally administrated ASH with three dosages (400, 200, and 100 mg/kg) for 6 weeks, and hepatic metabolomics based on gas chromatography-mass spectrometry (GC-MS) was carried out to identify differential metabolites and related metabolic pathways. Next, the integrated analysis of metabolomics and network pharmacology was applied to find the key target. Finally, molecular docking technology was employed to define the combination of the key target and the corresponding compounds. Results: A total of 13 metabolites and four related metabolic pathways were found in metabolomics analysis. From the combined analysis of network pharmacology and metabolomics, six targets (DAO, MAOA, MAOB, GAA, HK1, and PYGM) are the overlapping targets and two metabolic pathways (glycine, serine, and threonine metabolism and starch and sucrose metabolism) are the most related pathways. Finally, DAO, MAOA, MAOB, GAA, HK1, and PYGM were verified bounding well to their corresponding compounds including isofraxidin, eleutheroside B1, eleutheroside C, quercetin, kaempferol, and acacetin. Conclusion: Based on these results, it was implied that the potential mechanism of ASH on MDD was related to the regulation of metabolism of several excitatory amino acids and carbohydrates, as well as the expression of DAO, MAOA, MAOB, GAA, HK1, and PYGM.

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