J Appl Toxicol. 2026 Aug 23. doi: 10.1002/jat.70396. Online ahead of print.
ABSTRACT
Cantharidin (CTD) possesses potent anticancer activity, whereas its prominent hepatotoxicity severely limits its clinical application. Because the detailed molecular mechanisms responsible for CTD-triggered hepatotoxicity have not been fully elucidated, additional investigations are necessary to uncover its toxicological pathways. This study investigated the mechanism of CTD-triggered hepatotoxicity and the protective effects of exogenous glutathione (GSH) supplementation. In vitro 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-cysteine ligase modifier subunit (GCLM) expression, decreased mitochondrial membrane potential (MMP), suppressed B-cell lymphoma 2 (Bcl-2) expression, and upregulated Bcl-2-associated X protein (Bax), cysteine-dependent aspartate-directed protease (caspase-9), downstream caspase-3, and cytochrome c (Cyt c) levels, thereby triggering hepatocyte apoptosis, with no significant changes in cellular cysteine (Cys) content and glutamate-cysteine ligase catalytic subunit (GCLC) expression. In vivo 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-OEt) pretreatment in vitro and GSH intervention in vivo effectively prevented CTD-caused oxidative damage. Collectively, CTD induces divergent expression patterns of glutamate-cysteine ligase (GCL) subunits in vitro and in vivo, disrupts GSH metabolic homeostasis, and provokes oxidative stress and mitochondrial dysfunction, ultimately leading to hepatocellular injury.
PMID:42633976 | DOI:10.1002/jat.70396
