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Depression has a high morbidity and mortality worldwide, and because it is often accompanied by a series of complications, drugs that target a single protein or pathway may not fully exerts desired therapeutic effect. Traditional Chinese Medicine (TCM) plays a significant therapeutic effect in the treatment of depression and has fewer adverse reactions. However, taking a representative formula Chaihu Shugan Powder (CSP) as an example, which shows pharmacological effects on depression and its synergistic mechanism, remains still ambiguous. Our study aims to provide a holistic perspective of the correlation between TCM formula and depression, and to explore the synergistic mechanisms of CSP for the treatment of depression from multiple scales. In this study, we carry out systems pharmacology study on CSP by applying integrated of ADME evaluation, target fishing, protein-protein interaction analysis, gene ontology enrichment analysis, establishment of a directed network and network pharmacology analysis. As a result, 126 chemicals and 83 proteins are identified as active compounds and depression-related targets, and the synergistic effects of CSP formula for the treatment of depression are based on its three mechanisms of anti-inflammation, and the regulation of neuroendocrine system and monoamine neurotransmitter through the smooth operation of complex biological pathways, including especially PI3K-Akt, cAMP and MAPK signaling pathways. Moreover, network analysis reveals that CSP is also capable of relieving or even certainly eliminating side effects and complications of depression due to the abundant active ingredients in CSP formula. Conclusion: This work not only provides insights into the synergy of TCM for depression treatment, but also provides a new and effective way to develop potential antidepressants and targets.

Systems Pharmacology Dissection of Multi-Scale Synergistic Treatment Strategies of Chaihu Shugan Powder for Depression