Exploring the Therapeutic Efficacy of Xiaoyaosan in Alleviating Depression: A Mechanistic Insight into the Modulation of Microglial Oxidative Stress Response by Quercetin

Depression is a mental disorder with complicated causes and pathologies. Xiaoyaosan (XYS), a traditional Chinese medicine, has shown promise in depression treatment due to its multi-targeted approach and low side effects. Currently, there are relatively few research that provides a scientific understanding of XYS’s treatment mechanism. Here, we explored the potential mechanism to provide proof of XYS’s antidepressant effects using network pharmacology and in vitro experiments. Firstly, network pharmacology was conducted to screen key chemicals and potential targets within the major ingredients of XYS’s herbal formula. Predicted targets’ protein-protein interactions and pathway analysis revealed as the central component effecting multiple core targets shared by depression and XYS’s ingredients. Based on that, Quercetin was selected for further in vitro study. A microglial cell model was constructed to evaluate the antioxidant and anti-inflammatory effect of Quercetin under oxidative and bacterial stress induced by H₂O₂ and lipopolysaccharide, respectively. Results showed that Quercetin at appropriate concentrations (20 μM and 50 μM) could maintain microglial cell activation balance and mitochondrial function. Under stressful conditions, exposure to higher concentrations (100 μM) led to cellular morphological damage or apoptosis, but not in healthy or resting microglial cells. Our findings confirmed Quercetin’s beneficial impacts on microglial cell health, a critical aspect of depression pathology. This study integrated network pharmacology with in vitro experiments to provide evidence that XYS could mitigate inflammatory and oxidative responses of microglial cells implicated in depression, primarily through the modulating mitochondrial function and cellular morphology.