Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Evodiamine targets ZO-1 to ameliorate cholestatic liver disease: Intestinal homeostasis as the core mediator of gut-liver axis repair and bile acid metabolism remodeling.
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Yan Shuxin, Zhang Yao, Fan Qiqi, Jia Wenwen, Dai Yihang, Li Xinlin, Lu Shan, Sheng Yuhan, Sun Shuang, Lin Ruichao, Tang Yang, Zhao Chongjun
Аннотация
BACKGROUND: Cholestatic liver disease (CLD) is a complex and multifactorial chronic disorder that requires a systematic and integrative management. Evodiamine (EVO), a natural alkaloid derived from Evodiae Fructus, has demonstrated significant therapeutic potential in ameliorating digestive diseases. However, the beneficial effects of EVO on CLD and the underlying mechanisms remain poorly understood.
OBJECTIVE: This study aims to elucidate the mechanisms through which EVO modulates the progression of CLD, with a particular focus on the regulation of gut-liver axis homeostasis.
METHODS: The therapeutic efficacy of EVO in bile duct ligation (BDL)- and α-naphthyl isothiocyanate (ANIT)-induced CLD rat models was systematically evaluated. An integrative approach combining network pharmacology with multi-omics analyses (transcriptomic, metagenomic sequencing, targeted bile acid metabolomics) was employed to identify significantly altered molecular networks. Fecal microbiota transplantation (FMT) was conducted to validate the functional role of gut microbiota in the hepato-intestinal protective effects. Direct molecular targets as well as the functional validation were confirmed through molecular docking, pull-down assays, surface plasmon resonance and cellular thermal shift assay.
RESULTS: EVO achieved significant synchronous hepato-intestine protection in both CLD rats: it markedly ameliorated hepatic injury and hepatic fibrosis, downregulated pro-inflammatory cytokine levels, while preserving intestinal barrier integrity and alleviating intestinal inflammation. Mechanistically, EVO exerted these protective effects by directly targeting the tight junction protein ZO-1 and enhancing its expression and stability. Furthermore, EVO restored intestinal microbial homeostasis, corrected dysregulated BA metabolism-specifically normalizing deoxycholic acid (DCA) levels. FMT experiments demonstrated that the synchronous hepato-intestinal beneficial effects of EVO were partially mediated by gut microbiota.
CONCLUSION: EVO exerts a protective effect against CLD by directly targeting ZO-1 to strengthen intestinal barrier function, thereby restoring gut microbial balance and rebalancing BAs metabolism (especially DCA levels) in the gut-liver axis. This study uncovers a novel ZO-1-dependent mechanism of EVO in CLD, highlighting EVO as a promising candidate for the treatment of CLD and providing new insights into gut-liver axis-targeted therapies.
OBJECTIVE: This study aims to elucidate the mechanisms through which EVO modulates the progression of CLD, with a particular focus on the regulation of gut-liver axis homeostasis.
METHODS: The therapeutic efficacy of EVO in bile duct ligation (BDL)- and α-naphthyl isothiocyanate (ANIT)-induced CLD rat models was systematically evaluated. An integrative approach combining network pharmacology with multi-omics analyses (transcriptomic, metagenomic sequencing, targeted bile acid metabolomics) was employed to identify significantly altered molecular networks. Fecal microbiota transplantation (FMT) was conducted to validate the functional role of gut microbiota in the hepato-intestinal protective effects. Direct molecular targets as well as the functional validation were confirmed through molecular docking, pull-down assays, surface plasmon resonance and cellular thermal shift assay.
RESULTS: EVO achieved significant synchronous hepato-intestine protection in both CLD rats: it markedly ameliorated hepatic injury and hepatic fibrosis, downregulated pro-inflammatory cytokine levels, while preserving intestinal barrier integrity and alleviating intestinal inflammation. Mechanistically, EVO exerted these protective effects by directly targeting the tight junction protein ZO-1 and enhancing its expression and stability. Furthermore, EVO restored intestinal microbial homeostasis, corrected dysregulated BA metabolism-specifically normalizing deoxycholic acid (DCA) levels. FMT experiments demonstrated that the synchronous hepato-intestinal beneficial effects of EVO were partially mediated by gut microbiota.
CONCLUSION: EVO exerts a protective effect against CLD by directly targeting ZO-1 to strengthen intestinal barrier function, thereby restoring gut microbial balance and rebalancing BAs metabolism (especially DCA levels) in the gut-liver axis. This study uncovers a novel ZO-1-dependent mechanism of EVO in CLD, highlighting EVO as a promising candidate for the treatment of CLD and providing new insights into gut-liver axis-targeted therapies.