Abstract
Cantharidin (CTD) is a principal bioactive component of traditional Chinese medicine Mylabris used in cancer treatment. However, CTD clinical application is limited due to nephrotoxicity, and the mechanism is unknown. The present study used widely-targeted metabolomics, network pharmacology, and cell experiments to investigate the nephrotoxicity mechanism after CTD exposure. In mice exposed to CTD, serum creatinine and urea nitrogen levels increased with renal injury. Then, 74 differential metabolites were detected, including 51 up-regulated and 23 down-regulated metabolites classified as amino acids, small peptides, fatty acyl, arachidonic acid metabolite, organic acid, and nucleotides. Sixteen metabolic pathways including tyrosine, sulfur, and pyrimidine metabolism were all disrupted in the kidney. Furthermore, network pharmacology revealed that 258 metabolic targets, and pathway enrichment indicated that CTD could activate oxidative phosphorylation and oxidative stress (OS). Subsequently, HK-2cell experiments demonstrated that CTD could reduce superoxide dismutase while increasing malondialdehyde levels. In conclusion, after CTD exposure, biometabolic processes may be disrupted with renal injury in mice, resulting in oxidative phosphorylation and OS.
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