Chaihu Shugan San exerts antidepressant effects by driving microglial M2 polarization via inhibition of the IL-1β/JNK signaling pathway

Ren H, Liu K, Li J, Wang J, Wang H, Zhang T, Liu L, Gao Y, Qiang F, Qu Z, Zou X · Journal of Ethnopharmacology · 2026 April

DOI 10.1016/j.jep.2025.121137

Objective

To investigate the pharmacodynamic material basis of Chaihu Shugan San (CSS) responsible for its antidepressant effects and related immunomodulatory mechanisms.

Conclusions

The 95% ethanol extract of CSS (CSS-95) demonstrated robust antidepressant activity by modulating neurotransmitter levels, suppressing pro-inflammatory cytokines, and enhancing anti-inflammatory cytokines. CSS-95 inhibited microglial M1 polarization, promoted M2 polarization, and inhibited the IL-1β/JNK signaling pathway, contributing to its antidepressant effects.

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Insights

Chaihu Shugan San, a traditional Chinese medicine, shows potential antidepressant effects by suppressing neuroinflammation and favoring beneficial microglial polarization.

The methodology involved identifying the optimal active fraction of Chaihu Shugan San (CSS) through a screening using a reserpine-induced zebrafish model of depression. The chemical constituents were then analyzed by UPLC-Q-TOF-MS/MS. The advantages of this identified extract were further validated utilizing a corticosterone-induced mouse model of depression. The study utilized an integrated approach combining transcriptomics, network pharmacology, and molecular biology techniques to examine the immunomodulatory mechanisms underlying CSS' antidepressant effects. The results demonstrated the strongest antidepressant activity in a 95% ethanol extract of CSS, specifically enhancing behavioral parameters in depression models. This extract increased levels of mood-stabilizing neurotransmitters, decreased stress hormones, and modulated inflammatory response. Further investigation showed that CSS inhibited harmful microglial polarization and suppressed a key inflammation pathway. The study also identified 13 potential active components of the formula, seven of which showed promising results in the zebrafish model.