Systems Pharmacology and Multi-Omics Reveal Synergistic Antidepressant Mechanisms of Radix Bupleurum-Radix Paeoniae Alba via Oxidative Stress, Neuroimmune Balance, and Circadian Rhythm.

OBJECTIVE

Based on the classical TCM formulation from Shennong's Classic of Materia Medica, the Bupleuri Radix-Paeoniae Radix Alba (Chaihu-Baishao, CB) herb pair has long been used to treat depression-like disorders associated with liver stagnation syndrome (ganyu zheng), embodying the TCM principle of shugan jieyu (soothing the liver and relieving depression). This study aims to systematically decipher the multi-target mechanisms underlying CB's antidepressant effects, bridging traditional use with modern systems pharmacology.

METHODS

We employed integrated metabolomics-transcriptomics and behavioral validation in a rat model of chronic unpredictable mild stress (CUMS). Rats were treated with CB water extract for four weeks, and antidepressant effects were assessed through behavioral tests. Serum metabolomics and liver transcriptomics were performed, followed by bioinformatics integration and experimental validation.

RESULTS

CB treatment significantly improved depressive-like behaviors, reversing anhedonia and reducing despair. Multi-omics integration revealed CB's actions across three key mechanistic domains:.

OXIDATIVE STRESS: Regulation of glutathione metabolism, notably reducing oxidized glutathione.

NEUROIMMUNE BALANCE: Modulation of PI3K/AKT and AMPK/SIRT1 pathways, accompanied by decreased pro-inflammatory cytokines.

CIRCADIAN RHYTHM: Normalization of core clock genes such as Cry2 and Per2.

CONCLUSION

The CB herb pair exerts antidepressant effects through synergistic modulation of oxidative stress, neuroimmune balance, and circadian rhythm, providing a systems-level validation of the TCM concept of shugan jieyu. These findings highlight the translational potential of CB as an integrative treatment for depression and offer a modern pharmacological basis for classical TM formulations.