Study on the Antidepressant Effect and Mechanism of Water Extract of Semiliquidambar cathayensis (WESC) Based on the GSK3β/NF‐κB Signaling Pathway

Water extract of Semiliquidambar cathayensis (WESC) exhibits favorable therapeutic effects against depression, yet its pharmacodynamic material basis and mechanism of action remain unclear. In this study, ultra‐high‐performance liquid chromatography coupled with quadrupole time‐of‐flight mass spectrometry (UPLC‐Q‐TOF‐MS) was employed to analyze the chemical constituents of WESC. Network pharmacology and molecular docking were further applied to screen the antidepressant mechanism basis and potential targets of WESC. Lipopolysaccharide (LPS)‐induced mouse and PC12 cell models were established as in vivo depressive animal model and in vitro cellular injury model, respectively. Combined with pathological examination and molecular biological techniques, the antidepressant mechanism of WESC was systematically investigated. Results showed that a total of 14 chemical components were identified from WESC. Network pharmacology and molecular docking analyses indicated that GSK3β was one of the key targets, and the active components in WESC possessed strong binding affinities with GSK3β, Axin1, and NF‐κB. Pathological studies demonstrated that WESC significantly alleviated inflammatory infiltration in the mouse prefrontal cortex and hippocampal neuronal damage. Molecular biological analyses revealed that WESC markedly downregulated the expression of proteins related to the GSK3β/NF‐κB signaling pathway in LPS‐stimulated mice and PC12 cells, thereby attenuating neuroinflammation, promoting neural plasticity, and exerting antidepressant effects. Ultra‐high‐performance liquid chromatography coupled with quadrupole time‐of‐flight mass spectrometry (UPLC‐Q‐TOF‐MS) was used to characterize the chemical constituents of the water extract of Semiliquidambar cathayensis (WESC). Network pharmacology and molecular docking were applied to screen core active components and potential targets. An LPS‐induced mouse depression model and PC12 cell injury model were established. Combined with HE staining, Western blot, and qRT‐PCR, in vivo and in vitro experiments were carried out to explore the antidepressant mechanism of WESC via regulating signaling pathways and alleviating neuroinflammation.