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Fructus Psoraleae (FP), one of the significant traditional Chinese medicines, has been reported to cause hepatotoxicity. However, the mechanism remains undetermined and the reported research is limited. In this study, a tandem mass tag (TMT)-based quantitative proteomics and metabolomics were used to reveal a more comprehensive effect caused by FP. The results showed that aqueous extract of FP can induce liver injury in rats. In total, 575 significantly changed proteins were identified by quantitative proteomics analysis, among which 352 proteins were significantly up-regulated and 223 proteins were significantly down-regulated in liver tissues. And we detected 14 biomarkers such as succinic acid, hypoxanthine, l -carnitine, phenylalanine, glutathione, and glycoursodeoxycholic acid. Correlation analysis of altered metabolites and proteins exhibited the aberrant regulation of metabolic pathways including bile secretion, glutathione metabolism, purine metabolism, glycerophospholipid metabolism, TCA cycle and pyruvate metabolism, which indicated the disorder of bile acid metabolism, oxidative stress, energy metabolism and immune system. Notably, the changed proteins including Cyp7a1, FXR, SHP, BSEP, Sult2a1, Nceh1 in bile acid metabolism may play an essential role in the hepatotoxicity induced by aqueous extract of FP. In conclusion, integrative proteomics and metabolomics provide the potential mechanism of hepatotoxicity induced by FP. Fructus Psoraleae, a traditional Chinese medicine, is widely used in Asia for the treatment of osteoporosis and vitiligo. Recently, clinical and experimental reports reveal that FP can induce liver injury. However the mechanism of injury induced by FP is still unclear. In this study, we detected 352 significantly up-regulated proteins and 223 significantly down-regulated proteins in liver tissues by TMT-based quantitative proteomics. And 14 important metabolites were identified by metabolomics analysis. Through integrative analysis of the key metabolites and proteins, several metabolism pathways were selected, which implicated in bile acid metabolism, oxidative stress, energy metabolism, immune system. This is the first integrative study of proteomics and metabolomics for FP exposure, the finding clarified the potential mechanism of hepatotoxicity caused by FP and will promote rational use of FP in clinical application. Unlabelled Image • 575 proteins and 14 metabolites significantly changed in liver tissues after Fructus Psoraleae exposure. • Fructus Psoraleae can influence bile acid metabolism, oxidative stress, energy metabolism, and immune system. • FXR, BSEP, Sult2a1, Nceh1, SHP, Cyp7a1 may play an essential role in the mechanism of hepatotoxicity. [ABSTRACT FROM AUTHOR]