{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:09:53Z","timestamp":1785409793254,"version":"3.56.0"},"reference-count":60,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82574715"],"award-info":[{"award-number":["82574715"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82574715"],"award-info":[{"award-number":["82574715"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences","award":["KCQZ202400-KC-04-05"],"award-info":[{"award-number":["KCQZ202400-KC-04-05"]}]},{"name":"Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences","award":["CI2024E003"],"award-info":[{"award-number":["CI2024E003"]}]},{"name":"Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences","award":["CI2023E002"],"award-info":[{"award-number":["CI2023E002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tripterygium glycosides extract (TGE), the primary active component of tripterygium glycosides tablets, is widely used for immune-related disorders but raises significant clinical concerns regarding cholestatic drug-induced liver injury. As conventional models fail to fully recapitulate the complex pathogenesis of traditional Chinese medicine toxicity, this study aimed to elucidate the mechanisms of TGE-induced cholestatic injury using a biomimetic microfluidic liver-on-a-chip platform. The chip integrated rat precision-cut liver slices (PCLSs) and human endothelial cells (EA.hy926) to simulate the hepatic sinusoidal microenvironment. Following TGE exposure (15\u2013135 \u03bcg\/mL for 12 and 24 h), vascular barrier integrity was maintained, while liver injury markers (ALT, AST, TBA, DBIL) significantly increased in a dose- and time-dependent manner, accompanied by progressive histopathological deterioration in PCLSs. Mechanistically, TGE triggered severe oxidative stress (decreased SOD\/GSH\/GSH-Px and increased MDA) and upregulated pro-inflammatory cytokines (IL-4 and IL-1\u03b2). Consequently, the expression of the bile acid receptor FXR and transporters (BSEP and MRP2) was significantly downregulated. In conclusion, TGE induces cholestatic liver injury via a sequential pathway: oxidative stress initiates an immune-inflammatory response, which subsequently suppresses the FXR\/BSEP\/MRP2 axis. Future studies should focus on developing fully humanized liver-on-a-chip systems to further validate these mechanisms and improve clinical translational significance.<\/jats:p>","DOI":"10.3390\/ijms27094154","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T09:03:37Z","timestamp":1778144617000},"page":"4154","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tripterygium Glycosides Extract-Induced Hepatic Cholestasis: A Mechanistic Study Using a Microfluidic Liver-on-a-Chip System"],"prefix":"10.3390","volume":"27","author":[{"given":"Yifei","family":"Yang","sequence":"first","affiliation":[{"name":"Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8896-5162","authenticated-orcid":false,"given":"Ya","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6785-8485","authenticated-orcid":false,"given":"Yun","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Xia","sequence":"additional","affiliation":[{"name":"Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haijing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guozhuang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Gong","sequence":"additional","affiliation":[{"name":"Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Qi","sequence":"additional","affiliation":[{"name":"Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5372-4692","authenticated-orcid":false,"given":"Chun","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1230320","DOI":"10.1155\/2020\/1230320","article-title":"Tripterygium Glycosides Combined with Leflunomide for Rheumatoid Arthritis: A Systematic Review and Meta-Analysis","volume":"2020","author":"Yang","year":"2020","journal-title":"Evid. 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