Tran, Son Hung Zhang, Siqi Lee, Hyeon-Seong Hitayezu, Emmanuel Nguyen, Uyen Tran Tu Lee, Sohyun Kang, Suk Woo Park, Keunwan Kim, Sae Hun Kwon, Hak Cheol Cha, Kwanghyun Kwon, Jaeyoung Kim, Joonki Kang, Kyungsu 2026-01-13T07:00:15Z 2026-01-13T07:00:15Z 2026-01-12 2026-01 0944-7113 https://pubs.kist.re.kr/handle/201004/153979 Background Schisandrin C (SCC), a bioactive lignan compound derived from Schisandra chinensis (S. chinensis), has been demonstrated to promote intestinal health. However, the antidepressant activity of SCC and its impact on the gut‒brain axis have not been reported. Purpose This study aimed to investigate the antidepressant effects of SCC and elucidate its molecular mechanisms through modulation of the microbiota‒gut‒brain axis. Methods Artificial intelligence (AI)-based target protein prediction, network pharmacology analysis, and experimental validation using intestinal cells, Caenorhabditis elegans, and mice models were conducted. Targeted metabolomics, gut microbiota analyses, and molecular biology techniques were employed for mechanistic elucidation. Results SCC treatment effectively suppressed depressive-like behaviors in mice subjected to chronic unpredictable mild stress (CUMS). SCC upregulated brain-derived neurotrophic factor (BDNF) expression in the brain by regulating the AKT/CREB/BDNF signaling pathway. Additionally, integrated network pharmacology, molecular docking, and metabolomics analyses revealed that SCC significantly increased brain serotonin levels by inhibiting monoamine oxidase (MAO) activity. Furthermore, SCC increased the abundance of Akkermansia and Bifidobacterium, as observed both in the synthetic microbial community in vitro and in the gut microbiota in vivo. Additionally, SCC effectively alleviated intestinal barrier dysfunction and reduced intestinal inflammation in vitro in intestinal cells, in vivo in C. elegans infected with Bacteroides fragilis, and in vivo in the CUMS-induced mice model. Conclusion SCC improves depressive-like behaviors by modulating the microbiota‒gut‒brain axis. These findings underscore the potential of SCC as an effective therapeutic agent for depression. English Elsevier BV Schisandrin C alleviates depressive-like behaviors by modulating the AKT/CREB/BDNF pathway, the serotonin pathway of tryptophan metabolism, and the gut microbiota composition Article 10.1016/j.phymed.2025.157581 1 Phytomedicine, v.150 Phytomedicine 150 Y scie scopus 001650548600001 2-s2.0-105025457259 Plant Sciences Chemistry, Medicinal Integrative & Complementary Medicine Pharmacology & Pharmacy Plant Sciences Pharmacology & Pharmacy Integrative & Complementary Medicine Article PATHOPHYSIOLOGY AKT/CREB/BDNF pathway Tryptophan metabolism Gut microbiota Schisandrin C Depression