Integrated Metabolomics and Network Pharmacology Strategy-Driven Active Traditional Chinese Medicine Ingredients Discovery for the Alleviation of Cisplatin Nephrotoxicity

Renal injury is the main adverse reaction of cisplatin, and many traditional Chinese medicines (TCMs) were proven active against renal toxicity. Here, an integrated metabolomics and network pharmacology strategy was proposed to discover active TCM ingredients for the alleviation of cisplatin nephrotoxicity. First, by interrogating the Human Metabolome Database (HMDB) we collected targets connected to 149 cisplatin nephrotoxicity-related metabolites. Second, targets of kidney damage were obtained from the Therapeutic Target Database (TTD), PharmGKB, Online Mendelian Inheritance in Man (OMIM), and Genetic Association Database (GAD). Common targets of both dysregulated metabolites and kidney damage were then used for TCM active ingredient screening by applying the network pharmacology approach. Eventually, 22 ingredients passed screening criteria, and their antinephrotoxicity activity was assessed in human kidney tubular epithelial (HK2) cells. As a result, 14 ingredients were found to be effective, in which kaempferol showed relatively better activity. Further metabolomics analysis revealed that kaempferol exerted an antinephrotoxicity effect in rats by regulating amino acid, pyrimidine, and purine metabolism as well as lipid metabolism. Collectively, this proposed integrated strategy would promote the transformation of metabolomics research in the field of drug pair discovery for the purpose of reduced toxicity and increased efficiency.