Integrated metabolomics and network pharmacology to reveal the mechanism of Wenxiao Jieyu capsule in the treatment of depression

This study aimed to explore Wenxiao Jieyu Capsule's (WJC) antidepressant mechanisms via serum pharmacochemistry, network pharmacology, metabolomics, and experimental validation. Serum pharmacochemistry and network pharmacology were employed to predict the biological processes and pathway regulated by WJC. Chronic unpredictable mild stress (CUMS)-induced rat model of depression was to explore the antidepressant mechanisms of WJC. A total of 20 prototype compounds were identified. Network pharmacology identified 283 overlapping targets, showing significant enrichment in purine metabolism and the NOD-like receptor protein 3 (NLRP3) inflammasome pathway. In vivo, WJC improved serum profiles, attenuated CUMS-induced depression-like behaviors and neuronal injury in the prefrontal cortex (PFC). Furthermore, WJC downregulated the expression of purinergic receptors P₂X purinoceptor 7 (P₂X₇R) and adenosine A_2A receptor (A_2AR), upregulated adenosine A₁ receptor (A₁R) expression, and inhibited the activation of the NLRP3 inflammasome, as evidenced by decreased protein levels of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and cysteine-aspartic acid protease-1 (Caspase-1). Collectively, these findings indicate that WJC alleviating neuroinflammation in CUMS-induced depressive rats by modulating purine metabolism and suppressing NLRP3 inflammasome activation. It offering a foundation for further research and clinical applications.