{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T02:23:01Z","timestamp":1787538181763,"version":"build-2736575974"},"reference-count":54,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T00:00:00Z","timestamp":1787443200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T00:00:00Z","timestamp":1787443200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Cantharidin (CTD) possesses potent anticancer activity, whereas its prominent hepatotoxicity severely limits its clinical application. Because the detailed molecular mechanisms responsible for CTD\u2010triggered hepatotoxicity have not been fully elucidated, additional investigations are necessary to uncover its toxicological pathways. This study investigated the mechanism of CTD\u2010triggered hepatotoxicity and the protective effects of exogenous glutathione (GSH) supplementation. In\u00a0vitro results showed that CTD reduced the GSH\/glutathione disulfide (GSSG) ratio and the activities of catalase (CAT) and glutathione peroxidase (GPX) in hepatocytes, induced a compensatory upregulation of superoxide dismutase (SOD), and promoted malondialdehyde (MDA) accumulation. Additionally, CTD downregulated glutamate\u2010cysteine ligase modifier subunit (GCLM) expression, decreased mitochondrial membrane potential (MMP), suppressed B\u2010cell lymphoma 2 (Bcl\u20102) expression, and upregulated Bcl\u20102\u2010associated X protein (Bax), cysteine\u2010dependent aspartate\u2010directed protease (caspase\u20109), downstream caspase\u20103, and cytochrome c (Cyt c) levels, thereby triggering hepatocyte apoptosis, with no significant changes in cellular cysteine (Cys) content and glutamate\u2010cysteine ligase catalytic subunit (GCLC) expression. In\u00a0vivo experiments verified that CTD markedly decreased hepatic GSH and Cys levels and downregulated GCLC expression, whereas GCLM expression and hepatic Cyt c levels showed only a slight upward trend without statistical significance. Glutathione ethyl ester (GSH\u2010OEt) pretreatment in\u00a0vitro and GSH intervention in\u00a0vivo effectively prevented CTD\u2010caused oxidative damage. Collectively, CTD induces divergent expression patterns of glutamate\u2010cysteine ligase (GCL) subunits in\u00a0vitro and in\u00a0vivo, disrupts GSH metabolic homeostasis, and provokes oxidative stress and mitochondrial dysfunction, ultimately leading to hepatocellular injury.<\/jats:p>","DOI":"10.1002\/jat.70396","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T01:47:11Z","timestamp":1787536031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cantharidin Causes Hepatotoxicity by Disrupting GSH\u2010Mediated Redox Homeostasis"],"prefix":"10.1002","author":[{"given":"Hong","family":"Tang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial 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