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It is a promising dietary supplement for the treatment of depression based on TCM principles and nutritional assessments. Our study was designed to explore BCBL's antidepressant\u2010like effects and elucidate its underlying mechanisms. First, the antidepressant\u2010like effects of BCBL were predicted through network pharmacology and validated using systematic depression models. Next, the 5\u2010HTP\u2010induced head\u2010twitch test, yohimbine\u2010induced death test, and reserpine\u2010induced ptosis, hypothermia, and akinesia test were conducted to assess BCBL's impact on monoaminergic function. Additionally, the effects of BCBL on monoamine neurotransmitters were measured using HPLC\u2010ECD and ELISA. As a result, an integrated analysis using the TCMSP and Genecards databases identified 37 active components sharing 192 targets associated with depression. Further construction of the PPI network, along with GO and KEGG enrichment analyses, revealed a comprehensive and synergistic interaction between BCBL and depression, also predicting that the serotoninergic system might partially mediate the antidepressant\u2010like effects of BCBL. Subsequent pharmacological tests indicated that BCBL demonstrated significant antidepressant\u2010like effects on behavioral despair mice, CRS and CNE\u2010induced depression\u2010like mice, and chronic reserpine\u2010induced depression\u2010like mice. The DDI tests, HPLC\u2010ECD, and ELISA analyses validated that BCBL's antidepressant\u2010like effects were mediated through upregulation of the serotoninergic system. Our findings provided a safe and effective candidate for the amelioration of depression that deserves further investigations and explorations.<\/jats:p>","DOI":"10.1002\/fsn3.70819","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T11:18:47Z","timestamp":1756898327000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Baichuan Baile Formula, a Promising Herbal Dietary Supplement, Exerts Antidepressant\u2010Like Effects by Modulating the Serotoninergic System in Mouse Models"],"prefix":"10.1002","volume":"13","author":[{"given":"Shuai\u2010Ming","family":"Zhu","sequence":"first","affiliation":[{"name":"Beijing Institute of Pharmacology and Toxicology  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun\u2010Xue","family":"Gao","sequence":"additional","affiliation":[{"name":"Beijing Institute of Pharmacology and Toxicology  Beijing 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