Transcriptomics, Proteomics and Network Pharmacology Reveal the Mechanisms of Cantharidin-Induced Kidney Injury in Rats

Cantharidin (CTD), the principal active constituent of the traditional Chinese medicine (TCM) Mylabris, exhibits potent antitumor activity. However, its clinical application is limited by organ toxicity (especially nephrotoxicity), and the underlying mechanisms remain incompletely defined. This research endeavored to elucidate the nephrotoxic effects and molecular mechanisms of CTD in rats using serum biochemical assays, histopathological examinations, and a multi-omics strategy. CTD treatment significantly increased levels of urea nitrogen and creatinine and induced histopathological injury in the kidneys. Transcriptomics, proteomics, and network pharmacology integrated analysis have revealed 14 common targets, mainly involved in the glutathione metabolic pathway. Further verification showed that CTD markedly upregulated protein expression of glutaminase (GLS), while downregulating homogentisate 1,2-dioxygenase (HGD), glutamate-cysteine ligase catalytic subunit (GCLC), and regulatory subunit (GCLM), thereby suppressing the glutathione metabolic pathway and exacerbating kidney injury. Our results indicate that CTD induces oxidative stress and consequent nephrotoxicity by inhibiting the glutathione metabolic pathway, providing a mechanistic basis for optimizing clinical strategies to mitigate CTD-induced kidney injury.