{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T11:39:48Z","timestamp":1792669188160,"version":"4.5.0"},"reference-count":32,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T00:00:00Z","timestamp":1792627200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T00:00:00Z","timestamp":1792627200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82130120"],"award-info":[{"award-number":["82130120"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82004162"],"award-info":[{"award-number":["82004162"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82204592"],"award-info":[{"award-number":["82204592"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Phytotherapy Research"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Ajugol (AJ), the primary component extracted from the root of\n                    <jats:italic>Rehmannia glutinosa<\/jats:italic>\n                    , exhibits protective effects against metabolic dysregulation and chronic inflammation. This present work aims to study the therapeutic effect of AJ on liver fibrosis and to explore the underlying mechanism. Liver fibrosis was induced in C57BL\/6J mice through the administration of 15% CCl\n                    <jats:sub>4<\/jats:sub>\n                    , followed by intragastric dosing of AJ at 20 and 40\u2009mg\/kg. We conducted a comprehensive evaluation involving histopathological assessment, serum biochemistry, RNA sequencing, and targeted metabolomics. In\u00a0vitro models consisted of DCA\u2010stimulated AML12 and RAW264.7 cells. Compared to untreated fibrotic mice, AJ intervention decreased the levels of serum ALT and AST, as well as hepatic hydroxyproline, \u03b1\u2010SMA, and COL1A1. Transcriptomic analysis revealed that AJ significantly regulated key genes involved in primary bile acid (BA) biosynthesis and arachidonic acid (ARA) metabolism. AJ downregulated CYP7A1 expression and reduced the accumulation of toxic deoxycholic acid (DCA) in the mouse liver. Additionally, AJ decreased the expressions of COX\u20102, PTGR1, PTGR2, and HPGDS, as well as the levels of downstream metabolites prostaglandins PGD2 and PGE2, thereby improving ARA metabolism via the COX pathway. The anti\u2010inflammatory effects of AJ were evidenced by a decrease in pro\u2010inflammatory cytokines IL\u20101\u03b2, IL\u20106, TNF\u2010\u03b1, and macrophage markers such as F4\/80 and CD11b. In\u00a0vitro, AJ alleviated DCA\u2010induced hepatocellular injury and inhibited pro\u2010inflammatory cytokine production in macrophages. DCA inhibited nuclear FXR activation, impairing hepatocyte function and activating inflammatory response. AJ effectively restored these functions. AJ improved hepatic inflammation and fibrosis, partly by alleviating the harmful effects of toxic BA accumulation. This highlights AJ as a promising novel therapeutic agent for liver fibrosis.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70488","type":"journal-article","created":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T10:59:32Z","timestamp":1792666772000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ajugol Improves Liver Fibrosis by Modulating Bile Acid and Arachidonic Acid Metabolism in Mice"],"prefix":"10.1002","author":[{"given":"Xia","family":"Wei","sequence":"first","affiliation":[{"name":"Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2583-5862","authenticated-orcid":false,"given":"Fangyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine  Shanghai China"},{"name":"School of Pharmaceutical Sciences Zhejiang Chinese Medical University  Zhejiang Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine  Shanghai China"},{"name":"Department of Pharmacy The NATCM Third Grade Laboratory of Traditional Chinese Medicine Preparations, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longhui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The NATCM Third Grade Laboratory of Traditional Chinese Medicine Preparations, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feipeng","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaofeng","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine  Shanghai China"},{"name":"Department of Pharmacy The NATCM Third Grade Laboratory of Traditional Chinese Medicine Preparations, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,22]]},"reference":[{"issue":"1","key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.ajpath.2010.11.026","article-title":"Bile Acids Induce Inflammatory Genes in Hepatocytes: A Novel Mechanism of Inflammation During Obstructive Cholestasis","volume":"178","author":"Allen K.","year":"2011","journal-title":"American Journal of Pathology"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.bcp.2021.114732","article-title":"Role of Eicosanoids in Liver Repair, Regeneration and Cancer","volume":"192","author":"Alvarez M. L.","year":"2021","journal-title":"Biochemical Pharmacology"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.jep.2022.116132","article-title":"Extraction, Structure and Bioactivities of Polysaccharides From Rehmannia glutinosa: A Review","volume":"305","author":"Bian Z.","year":"2023","journal-title":"Journal of Ethnopharmacology"},{"issue":"8","key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1007\/s10529-012-0932-5","article-title":"Relationship Between Bile Salt Hydrolase Activity, Changes in the Internal pH and Tolerance to Bile Acids in Lactic Acid Bacteria","volume":"34","author":"Bustos A. Y.","year":"2012","journal-title":"Biotechnology Letters"},{"key":"e_1_2_10_6_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.pharmthera.2022.108238","article-title":"Bile Acid Metabolism and Signaling, the Microbiota, and Metabolic Disease","volume":"237","author":"Cai J.","year":"2022","journal-title":"Pharmacology & Therapeutics"},{"issue":"8","key":"e_1_2_10_7_1","doi-asserted-by":"crossref","first-page":"737","DOI":"10.21037\/atm-20-5110","article-title":"The Role of Bile Acids in Cholestatic Liver Injury","volume":"9","author":"Cai S. Y.","year":"2021","journal-title":"Annals of Translational Medicine"},{"issue":"4","key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/s41579-022-00805-x","article-title":"Bile Acids and the Gut Microbiota: Metabolic Interactions and Impacts on Disease","volume":"21","author":"Collins S. L.","year":"2023","journal-title":"Nature Reviews. Microbiology"},{"issue":"2","key":"e_1_2_10_9_1","doi-asserted-by":"crossref","first-page":"111","DOI":"10.3109\/07357907.2012.762781","article-title":"Bile Acids Affect the Growth of Human Cholangiocarcinoma via NF\u2010kB Pathway","volume":"31","author":"Dai J.","year":"2013","journal-title":"Cancer Investigation"},{"issue":"4","key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"411","DOI":"10.3233\/CBM-170157","article-title":"Pioglitazone Suppresses Inflammation and Fibrosis in Nonalcoholic Fatty Liver Disease by Down\u2010Regulating PDGF and TIMP\u20102: Evidence From In\u00a0Vitro Study","volume":"20","author":"Deng W.","year":"2017","journal-title":"Cancer Biomarkers"},{"issue":"7","key":"e_1_2_10_11_1","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1038\/s41575-021-00566-7","article-title":"Role of Bile Acids and Their Receptors in Gastrointestinal and Hepatic Pathophysiology","volume":"19","author":"Fuchs C. D.","year":"2022","journal-title":"Nature Reviews Gastroenterology & Hepatology"},{"issue":"10","key":"e_1_2_10_12_1","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/s41575-023-00807-x","article-title":"Hepatic Inflammatory Responses in Liver Fibrosis","volume":"20","author":"Hammerich L.","year":"2023","journal-title":"Nature Reviews. Gastroenterology & Hepatology"},{"issue":"7835","key":"e_1_2_10_13_1","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/s41586-020-2938-9","article-title":"Fibrosis: From Mechanisms to Medicines","volume":"587","author":"Henderson N. C.","year":"2020","journal-title":"Nature"},{"key":"e_1_2_10_14_1","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/978-1-4939-6346-1_5","article-title":"Transactivation and Coactivator Recruitment Assays for Measuring Farnesoid X Receptor Activity","volume":"1473","author":"Hsu C. W.","year":"2016","journal-title":"Methods in Molecular Biology"},{"issue":"2","key":"e_1_2_10_15_1","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1002\/hep.28965","article-title":"The Ascending Pathophysiology of Cholestatic Liver Disease","volume":"65","author":"Jansen P. 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J.","year":"2019","journal-title":"Toxicology In\u00a0Vitro"},{"issue":"29","key":"e_1_2_10_19_1","doi-asserted-by":"crossref","first-page":"21805","DOI":"10.1074\/jbc.C000275200","article-title":"Bile Acid Induction of Cytokine Expression by Macrophages Correlates With Repression of Hepatic Cholesterol 7\u03b1\u2010Hydroxylase","volume":"275","author":"Miyake J. H.","year":"2000","journal-title":"Journal of Biological Chemistry"},{"issue":"3","key":"e_1_2_10_20_1","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.jep.2011.12.028","article-title":"Inhibitory Effects of Scutellaria Baicalensis Extract on Hepatic Stellate Cells Through Inducing G2\/M Cell Cycle Arrest and Activating ERK\u2010Dependent Apoptosis via Bax and Caspase Pathway","volume":"139","author":"Pan T. L.","year":"2012","journal-title":"Journal of Ethnopharmacology"},{"issue":"4","key":"e_1_2_10_21_1","doi-asserted-by":"crossref","DOI":"10.3390\/cells9040875","article-title":"Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives","volume":"9","author":"Roehlen N.","year":"2020","journal-title":"Cells"},{"issue":"22","key":"e_1_2_10_22_1","doi-asserted-by":"crossref","first-page":"11686","DOI":"10.1039\/D1FO02657G","article-title":"Piperine Inhibits AML\u201012 Hepatocyte EMT and LX\u20102 HSC Activation and Alleviates Mouse Liver Fibrosis Provoked by CCl 4: Roles in the Activation of the Nrf2 Cascade and Subsequent Suppression of the TGF\u2010\u03b21\/Smad Axis","volume":"12","author":"Shu G.","year":"2021","journal-title":"Food & Function"},{"issue":"1","key":"e_1_2_10_23_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.jhep.2015.02.039","article-title":"Hepatic Fibrosis: Concept to Treatment","volume":"62","author":"Trautwein C.","year":"2015","journal-title":"Journal of Hepatology"},{"key":"e_1_2_10_24_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.jep.2024.117893","article-title":"Identification of Erzhu Jiedu Recipe and Its Molecular Mechanism Underlying Inhibited Human Hepatoma Cells by UHPLC\u2010Q\u2010Exactive Orbitrap HRMS and Network Pharmacology","volume":"325","author":"Wang F.","year":"2024","journal-title":"Journal of Ethnopharmacology"},{"issue":"31","key":"e_1_2_10_25_1","doi-asserted-by":"crossref","first-page":"5061","DOI":"10.2174\/0109298673288458240203064112","article-title":"Natural Products in Liver Fibrosis Management: A Five\u2010Year Review","volume":"31","author":"Wang T.","year":"2024","journal-title":"Current Medicinal Chemistry"},{"issue":"5","key":"e_1_2_10_26_1","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1002\/hep.22519","article-title":"Farnesoid X Receptor Antagonizes Nuclear Factor kappaB in Hepatic Inflammatory Response","volume":"48","author":"Wang Y. 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L.","year":"2016","journal-title":"Basic & Clinical Pharmacology & Toxicology"},{"issue":"1","key":"e_1_2_10_28_1","doi-asserted-by":"crossref","DOI":"10.1186\/s13020-023-00824-7","article-title":"Ajugol's Upregulation of TFEB\u2010Mediated Autophagy Alleviates Endoplasmic Reticulum Stress in Chondrocytes and Retards Osteoarthritis Progression in a Mouse Model","volume":"18","author":"Wu J.","year":"2023","journal-title":"Chinese Medicine"},{"key":"e_1_2_10_29_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.jep.2023.117514","article-title":"Recent Progress on the Application of Compound Formulas of Traditional Chinese Medicine in Clinical Trials and Basic Research In\u00a0Vivo for Chronic Liver Disease","volume":"321","author":"Xu F.","year":"2024","journal-title":"Journal of Ethnopharmacology"},{"issue":"5","key":"e_1_2_10_30_1","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1166\/mex.2023.2420","article-title":"Ajugol Attenuates Renal Injury in Multiple Myeloma by Blocking LILRB4 Signaling Pathway to Reduce PFKFB3 Expression","volume":"13","author":"Xu R.","year":"2023","journal-title":"Materials Express"},{"key":"e_1_2_10_31_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.phymed.2022.154345","article-title":"A Novel Iridoid Glycoside Leonuride (Ajugol) Attenuates Airway Inflammation and Remodeling Through Inhibiting Type\u20102 High Cytokine\/Chemokine Activity in OVA\u2010Induced Asthmatic Mice","volume":"105","author":"Yi L.","year":"2022","journal-title":"Phytomedicine"},{"key":"e_1_2_10_32_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.phrs.2021.105964","article-title":"Ajugol Enhances TFEB\u2010Mediated Lysosome Biogenesis and Lipophagy to Alleviate Non\u2010Alcoholic Fatty Liver Disease","volume":"174","author":"Zhang H.","year":"2021","journal-title":"Pharmacological Research"},{"issue":"16","key":"e_1_2_10_33_1","doi-asserted-by":"crossref","first-page":"4882","DOI":"10.1016\/j.bmc.2011.06.069","article-title":"Effects of \u03b2\u2010Glucosidase Hydrolyzed Products of Harpagide and Harpagoside on Cyclooxygenase\u20102 (COX\u20102) In\u00a0Vitro","volume":"19","author":"Zhang L.","year":"2011","journal-title":"Bioorganic & Medicinal Chemistry"}],"container-title":["Phytotherapy Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ptr.70488","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ptr.70488","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ptr.70488","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T10:59:37Z","timestamp":1792666777000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ptr.70488"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,22]]},"references-count":32,"alternative-id":["10.1002\/ptr.70488"],"URL":"https:\/\/doi.org\/10.1002\/ptr.70488","archive":["Portico"],"relation":{},"ISSN":["0951-418X","1099-1573"],"issn-type":[{"value":"0951-418X","type":"print"},{"value":"1099-1573","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,22]]},"assertion":[{"value":"2025-05-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"ptr.70488"}}