{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T18:04:44Z","timestamp":1770746684720,"version":"3.49.0"},"reference-count":64,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T00:00:00Z","timestamp":1770508800000},"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":["82304699"],"award-info":[{"award-number":["82304699"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Key Project at Central Government Level","award":["2060302"],"award-info":[{"award-number":["2060302"]}]},{"DOI":"10.13039\/501100017683","name":"Dalian Science and Technology Innovation Fund","doi-asserted-by":"publisher","award":["2025JJ11PT003"],"award-info":[{"award-number":["2025JJ11PT003"]}],"id":[{"id":"10.13039\/501100017683","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Acetaminophen (APAP) overdose is a major global cause of drug-induced liver injury (DILI), and the rising incidence of APAP-induced hepatotoxicity has raised substantial concern in the medical community, highlighting an urgent need for effective therapeutic approaches. Coptidis Rhizoma alkaloids (CRAs) have shown hepatoprotective effects in multiple hepatic disease models. This study aimed to investigate the therapeutic efficacy and the underlying mechanisms of CRA in acetaminophen (APAP)-induced acute liver injury. After identifying 18 alkaloid components in CRA, we employed an integrated strategy of untargeted metabolomics and network pharmacological analysis to investigate the underlying mechanisms. The potential mechanisms were subsequently validated through histopathological examination and molecular biology assays. Our results showed that CRA exerted dose-dependent protection against APAP-induced liver injury in vitro and in vivo. This protective effect was mediated by enhanced hepatic glutathione (GSH) biosynthesis via increased intracellular cysteine (Cys) availability. In the mouse model, hepatic Cys and GSH levels were increased by 2.2-fold and 1.8-fold, respectively, relative to the model group, which consequently attenuated oxidative stress damage. Furthermore, CRA suppressed APAP-induced activation of ERK and NF-\u03baB, reducing the phosphorylation levels by 39.2% and 38.0%, respectively. Accordingly, it also downregulated the subsequent expression of inflammatory mediators in the TNF signaling pathway. These findings provide crucial mechanistic insights into the hepatoprotective role of CRA against APAP-induced toxicity, establishing a valuable foundation for developing novel therapeutic or preventive strategies for APAP-induced liver injury.<\/jats:p>","DOI":"10.3390\/antiox15020223","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T09:41:02Z","timestamp":1770630062000},"page":"223","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Coptidis Rhizoma Alkaloids Alleviate Acetaminophen-Induced Liver Injury by Regulating GSH Metabolism and the TNF Signaling Pathway"],"prefix":"10.3390","volume":"15","author":[{"given":"Xiaoyao","family":"Ma","sequence":"first","affiliation":[{"name":"College of Life and Health, Dalian University, Dalian 116622, China"},{"name":"Dalian Institute of Marine Traditional Chinese Medicine, Dalian 116622, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiali","family":"Rao","sequence":"additional","affiliation":[{"name":"College of Life and Health, Dalian University, Dalian 116622, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuefei","family":"Li","sequence":"additional","affiliation":[{"name":"College of Life and Health, Dalian University, Dalian 116622, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zibin","family":"Li","sequence":"additional","affiliation":[{"name":"College of Life and Health, Dalian University, Dalian 116622, China"},{"name":"The Dalian Animal Virus Antigen Epitope Screening and Protein Engineering Drug Developing Key Laboratory, Dalian 116622, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuan","family":"Lu","sequence":"additional","affiliation":[{"name":"College of Life and Health, Dalian University, Dalian 116622, China"},{"name":"Dalian Institute of Marine Traditional Chinese Medicine, Dalian 116622, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yujie","family":"Lu","sequence":"additional","affiliation":[{"name":"College of Life and Health, Dalian University, Dalian 116622, China"},{"name":"Dalian Institute of Marine Traditional Chinese Medicine, Dalian 116622, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Guo","sequence":"additional","affiliation":[{"name":"Dalian Institute of Marine Traditional Chinese Medicine, Dalian 116622, China"},{"name":"National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baomin","family":"Feng","sequence":"additional","affiliation":[{"name":"College of Life and Health, Dalian University, Dalian 116622, China"},{"name":"Dalian Institute of Marine Traditional Chinese Medicine, Dalian 116622, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Zhao, M., Ma, J., Li, M., Zhang, Y., Jiang, B., Zhao, X., Huai, C., Shen, L., Zhang, N., and He, L. 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