Integration of transcriptomics and metabolomics to reveal crizotinib-induced liver injury in mice

Area of Science:

• Hepatology
• Oncology
• Toxicology

Background:

• Drug-induced liver injury (DILI) is a significant cause of acute liver failure.
• Crizotinib is a vital treatment for non-small cell lung cancer (NSCLC) with specific genetic mutations (c-MET, ALK, ROS1).
• The mechanisms behind crizotinib-induced hepatotoxicity are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms of liver injury caused by crizotinib.
• To investigate the role of ferroptosis in crizotinib-induced hepatotoxicity.
• To identify key metabolic pathways involved in this adverse drug reaction.

Main Methods:

• Integrated transcriptomic and metabolomic analyses in a mouse model.
• Administration of crizotinib (500 mg/kg) for two consecutive days.
• Assessment of plasma transaminase levels, hepatic lipid peroxidation, and cell death markers.

Main Results:

• Crizotinib administration led to elevated transaminase levels, increased hepatic lipid peroxidation, and cell death in mice.
• Multi-omics data indicated that crizotinib induces ferroptosis.
• Key affected pathways include cholesterol metabolism, glutathione metabolism, oxidative phosphorylation, and iron ion transport.
• Alterations in RNA methylation may contribute to crizotinib-induced ferroptosis.

Conclusions:

• Ferroptosis is a critical mechanism underlying crizotinib-induced liver injury.
• The study provides novel insights into the adverse drug reaction mechanisms of crizotinib.
• Understanding these pathways can inform strategies to mitigate crizotinib hepatotoxicity.