Widely Targeted Liver Metabolomics Reveals Potential Biomarkers in Mice with Drug-Induced Liver Injury

TL;DR

This study identifies potential biomarkers for drug-induced liver injury in mice using metabolomics, offering a new approach for early diagnosis.

Contribution

The study provides a novel metabolomic signature from injured liver tissue for early detection of drug-induced liver injury.

Findings

41 differentially expressed metabolites were identified, mainly involved in key metabolic pathways like glycerophospholipid and glutathione metabolism.

11 metabolites showed high AUC values (>0.90) in ROC analysis, suggesting strong potential as DILI biomarkers.

Elevated ALT and AST levels confirmed the successful DILI model in mice.

Abstract

Background: Drug-induced liver injury (DILI), a major type of adverse drug reaction, has become one of the leading causes of acute liver injury and liver failure worldwide. Its clinical significance lies not only in acute hepatocyte necrosis and functional failure but also in its role as a key initiating factor for liver cancer progression. Therefore, early diagnosis of DILI is of great importance. Methods: This study employed ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) to perform widely targeted metabolomics analysis on acetaminophen (APAP)-induced liver injury mice and healthy mice. Results: UPLC-QTRAP-MS/MS identified 41 differentially expressed metabolites primarily involved in glycerophospholipid metabolism, arginine and proline metabolism, primary bile acid biosynthesis, and glutathione metabolism pathways. The significant elevation of serum and hepatic alanine aminotransferase (ALT) and aspartate aminotransferase (AST) confirmed the successful establishment of the drug-induced liver injury (DILI) model. ROC curve analysis indicated 11 metabolites with AUC values exceeding 0.90 as potential biomarkers, including (R)-2-Hydroxybutyric acid, Glu-Gln, γ-Glu-Gln, 2-Methyllactic acid, L-Serine, Hyodeoxycholic acid, 3-Epideoxycholic acid, and Glycochenodeoxycholic acid 7-sulfate. Conclusions: We propose that these differential metabolites may serve as candidate biomarkers for DILI. Our findings provide a novel metabolomic signature derived directly from the injured tissue and offer a theoretical foundation for further research into early diagnosis of drug-induced liver injury.

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