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The present study aimed to identify the active compounds from the well-documented herbal medicine formula Banxia-Houpo decoction (BHD) and discover the underlying mechanisms for tuning microglia. We initially employed Liquid chromatography\u2013mass spectrometry (LC-MS) profiling and network pharmacology analysis to predict the active compound\u2013target interaction networks. We subsequently validated the potential active compounds and targets in a mouse model of corticosterone (CORT)-induced depression and postsynaptic microglia BV2 cells. As a result, 64 compounds were identified in the ethanolic Banxia-Houpo decoction extract and predicted to target 25 depression-related genes. Interestingly, the serotonergic synapse pathway received the highest enrichment score while 5-hydroxytryptamine receptor 1A (HTR1A) was targeted by 6 compounds (i.e. baicalein, luteolin, N-nornuciferine, roemerine, scutellarin, and 6-shogaol). In parallel assays, a six-compound combo (SCC) and Banxia-Houpo decoction markedly ameliorated the depressive-like behaviors in corticosterone-lesioned mice and well-protected highly differentiated (HD) PC12 cells against corticosterone challenge. Moreover, six-compound combo and Banxia-Houpo decoction effectively induced hydroxytryptamine receptor 1A expression in mice and postsynaptic microglia BV2 cells. Hydroxytryptamine receptor 1A antagonist WAY-100635 at 1\u2005mg\/kg\/d via intraperitoneal injection attenuated the effects of six-compound combo and Banxia-Houpo decoction on the depressive behaviors in mice. These results suggest that six-compound combo might be a potential remedy against depression and other neurological disorders via targeting hydroxytryptamine receptor 1A in microglia.<\/jats:p>","DOI":"10.1093\/jleuko\/qiae167","type":"journal-article","created":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T02:03:28Z","timestamp":1722477808000},"source":"Crossref","is-referenced-by-count":5,"title":["Six-compound combo remedy ameliorates corticosterone-induced depressive behaviors in mice via targeting 5-hydroxytryptamine receptor 1A signaling"],"prefix":"10.1093","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8813-5861","authenticated-orcid":false,"given":"Yilu","family":"Sun","sequence":"first","affiliation":[{"name":"School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong , 3 Sassoon Road, Pokfulam, Hong Kong, 999077 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Shing Faculty of Medicine, The University of Hong Kong , 3 Sassoon Road, Pokfulam, Hong Kong, 999077 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3545-2811","authenticated-orcid":false,"given":"Jianhui","family":"Rong","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong , 3 Sassoon Road, Pokfulam, Hong Kong, 999077 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,7,31]]},"reference":[{"issue":"10189","key":"2025021510170137300_qiae167-B1","doi-asserted-by":"publisher","first-page":"e42","DOI":"10.1016\/s0140-6736(18)32408-5","article-title":"Reducing the global burden of depression: a Lancet-World Psychiatric Association 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