A Cooperative Strategy of Hippocampus Lipidomics and Anti‐Inflammatory Analysis to Evaluate the Antidepressant Effect of Zhi‐Zi‐Chi Decoction on CUMS Mice

In this study, Balb/c mice were subjected to chronic unpredictable mild stress (CUMS) and treated with Zhi-zi-chi Decoction (ZZCD). Using a hippocampal lipidomics approach that combined ultra performance liquid chromatography (UPLC)-Q-Exactive Orbitrap MS with multivariate statistical techniques and targeted metabolic pathway analysis, we identified potential lipid metabolites and pathways associated with depression. Meanwhile, anti-inflammatory analyses were conducted in the hippocampus of mice. The chromatograms revealed that most lipids of the same class eluted within the same time period. In the scatter plot, the control and CUMS groups were obviously separated, whereas the ZZCD-treated or fluoxetine-treated groups were positioned between them. In positive and negative ion modes, a comprehensive screening identified 130 differential lipid metabolites, which were classified into 5 groups and 17 types. ZZCD was hypothesized to have a certain call-back efficiency for some differential lipid metabolites. The study identified three target metabolic pathways with certain influence values: glycerophosphate metabolism, linoleic acid metabolism, and α-linolenic acid metabolism. Although ZZCD's inhibitory effect on IL-6 was not significant, it demonstrated good therapeutic effects in reducing central system inflammation associated with IL-1β and TNF-α. The research suggested that the pathogenesis of depression might be closely related to lipid metabolism. ZZCD exhibited antidepressant effects by regulating endogenous lipid metabolism in CUMS mice.