Background: Postmenopausal osteoporosis (PMOP) is a common metabolic bone disorder characterized by disrupted bone remodeling due to estrogen deficiency. Erxian Decoction (EXD), a traditional Chinese medicine formula, has shown clinical efficacy against PMOP, but its bioactive constituents and molecular mechanisms remain elusive. Methods: The therapeutic effects of EXD were evaluated in ovariectomized (OVX) mice using micro-CT and bone histomorphometry. Absorbed constituents of EXD were identified by UHPLC-Q analysis. Network pharmacology and quantitative proteomics were integrated to predict the key pathways and targets. The candidate target was validated by in vivo assays, including Western blot, glutathione (GSH) levels, glutathione S-transferases (GSTs) activity, malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE) levels. Molecular docking was performed to assess the binding affinity between bioactive components and the target protein. Results: EXD treatment significantly ameliorated bone microarchitecture deterioration and restored bone remodeling balance in OVX mice. A total of 137 core absorbed constituents of EXD were identified. Integrated network pharmacology and proteomics analyses revealed that EXD primarily modulates the glutathione metabolism pathway to counteract oxidative stress. Glutathione S-transferase A1 (GSTA1) was pinpointed as a potential target. In vivo experiments confirmed that EXD upregulated GSTA1 expression, restored total GSTs activity, replenished GSH reserves, and reduced MDA and 4-HNE levels. Molecular docking demonstrated stable protein–ligand interactions between bioactive components of EXD and GSTA1. Conclusions: EXD alleviates PMOP by activating GSTA1-mediated glutathione metabolism and suppressing oxidative stress. These findings provide a mechanistic basis for the clinical application of EXD in treating PMOP.
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