Zhizi Baipi Decoction Alleviates 3,5-Diethoxycarbonyl-1,4-dihydrocollidine-Induced Cholestatic Cholangiopathy and Fibrosis in Mice via the Hippo/Yes-Associated Protein Pathway.

Authors

Hongyan Hai, Jingwen Mai, Jingyi Wang, Guangzhen Zheng, Changhui Liu

Published in

Journal of ethnopharmacology. Pages 122301. Aug 17, 2026. Epub Aug 17, 2026.

Abstract

Cholestasis-induced liver diseases present with complex symptoms, exhibit significant individual variation in clinical treatment outcomes, and show diverse disease progression and prognoses, making them a key clinical focus in the field of hepatology. Zhizi Baipi Decoction (ZBP), derived from Treatise on Cold Damage Diseases, is used to treat jaundice. Composed of three Chinese herbal ingredients-Gardenia jasminoides J.Ellis, Phellodendron chinense C.K.Schneid., and Glycyrrhiza uralensis Fisch. ex DC., this formula has been confirmed to be effective against cholestatic liver disease by clinical studies; however, its active components and hepatoprotective mechanisms remain unclear.
This study aimed to explore the therapeutic effects and underlying molecular mechanisms of ZBP and its key active ingredient liquiritin against cholestatic liver injury.
A DDC diet-induced mouse model of cholestatic liver injury was established in this study. Multiple experimental approaches, including histopathological staining, ELISA, qPCR, Western blotting, 16S rRNA gut microbiota sequencing, transcriptome sequencing, and LC-MS analysis, were applied to systematically evaluate the protective effects of ZBP and liquiritin on hepatic dysfunction, biliary injury, liver fibrosis, bile acid metabolic disorder, and gut microbiota dysbiosis. Molecular docking and cellular thermal shift assay (CETSA) were performed to verify the binding affinity between active components and core target proteins. In vivo and in vitro experiments were further conducted to validate the regulatory mechanisms.
ZBP significantly ameliorated DDC-induced biliary lesions, hepatic inflammation, liver fibrosis, bile acid metabolic disturbance, and gut dysbiosis in cholestatic mice. Transcriptomic profiling combined with qPCR and Western blot validation identified the Hippo/YAP signaling pathway as the core regulatory axis responsible for ZBP-mediated hepatoprotection. LC-MS and molecular docking results indicated that liquiritin was a major bioactive component of ZBP with high binding affinity to key Hippo/YAP-related proteins. Further in vivo experiments demonstrated that liquiritin remarkably alleviated cholestasis-triggered biliary injury, hepatic inflammation, fibrosis, and abnormal bile acid metabolism. Consistently, in vivo tissue detection and in vitro cell experiments confirmed that liquiritin exerted protective effects against cholestatic liver damage by modulating the Hippo/YAP signaling pathway.
Collectively, ZBP and its major bioactive constituent liquiritin effectively ameliorate DDC-induced cholestatic liver injury via regulation of the Hippo/YAP signaling cascade. These findings provide novel experimental evidence and potential therapeutic targets for the clinical application of ZBP in the treatment of cholestatic liver diseases.

PMID:
42607876
Bibliographic data and abstract were imported from PubMed on 18 Aug 2026.

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