Targeted Metabolomics and Network Pharmacology to Screen Endogenous Biomarkers Indicating Dose‐Dependent Liver Injury Induced by Genipin and the Mechanism Uncovered

Genipin is the primary active pharmacological component of several commonly used traditional Chinese medicines, and it has a variety of applications. In addition to medical uses, it has applications in food and biomaterials. However, because genipin causes dose-dependent hepatotoxicity, it is critical to identify sensitive indicators of genipin-induced dose-dependent hepatotoxicity and explain its mechanism to prevent and treat hepatotoxicity caused by genipin and similar traditional Chinese medicines. This article uses targeted metabolomics, network pharmacology, and molecular docking to screen highly relevant early diagnostic markers of genipin-induced dose-dependent liver injury and then analyzes its toxicological targets to elucidate the mechanism of genipin-induced dose-dependent liver injury. The findings demonstrated that genipin's impact on the associated liver injury targets (GSR, AKR1B1, PTGS1, MAOB, CA2, HSP90AA1, CDK1, LGALS3, HTR2C, LCK, and CASP1) was primarily linked to its disturbance of the metabolic homeostasis of the endogenous metabolites 2-phenylpropionate, 4-hydroxybenzoic acid, propionylcarnitine, and N-acetylaspartic acid. This study serves as a foundation for the early detection and prevention of liver damage brought on by genipin and associated traditional Chinese medicines. It also serves as a guide for further in-depth research into the mechanism underlying genipin-induced liver injury.