Study on the mechanism of hepatotoxicity of Aucklandiae radix through liver metabolomics and network pharmacology.

Background: Aucklandiae Radix (CAR) and its roasted processed products (PAR) are extensively used in various Chinese patent medicines due to their diverse pharmacological activities. However, numerous side effects of CAR have been reported and the hepatotoxicity and the corresponding mechanisms have not been thoroughly investigated. Our study aims to explore the underlying mechanism of the hepatotoxic impacts of CAR. Methods: In this study, metabolomic analysis was performed using liver tissue from the mice administered with different dosages of CAR/PAR extracts to examine the hepatotoxic impacts of CAR and elucidate the underlying mechanism. Network pharmacology was employed to predict the potential molecular targets and associated signaling pathways based on the distinctive compounds between CAR and PAR. A composition-target-GO-Bio process-metabolic pathway network was constructed by integrating the hepatotoxicity-related metabolic pathways. Finally, the target proteins related with the hepatotoxic effect of CAR were identified and validated in vivo. Results: The metabolomics analysis revealed that 33 related metabolic pathways were significantly altered in the high-dose CAR group, four of which were associated with the hepatotoxicity and could be alleviated by PAR. The network identified NQO1 as the primary target of the hepatotoxic effect induced by CAR exposure, which was subsequently verified by Western Blotting. Further evidence in vivo demonstrated that Nrf2 and HO-1, closely related to NQO1, were also the main targets through which CAR induced the liver injury, and that oxidative stress should be the primary mechanism for the CAR-induced hepatotoxicity. Conclusions: This preliminary study on the hepatic toxic injury of CAR provides a theoretical basis for the rational and safe use of CAR rationally and safely in clinical settings.