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

Drug-induced liver injury is a major cause of acute liver failure. Crizotinib is a first-line treatment for patients with cellular-mesenchymal epithelial transition factor (c-MET), anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS1)-positive non-small cell lung Cancer. Although some patients treated with crizotinib experience hepatic adverse effects, the underlying mechanisms remain unclear. In this study, we integrated transcriptomic and metabolomic approaches to understand the molecular mechanisms of crizotinib-induced liver injury. After administering 500 mg/kg of crizotinib via gavage for two consecutive days, we observed elevated transaminase levels in mouse plasma, accompanied by increased hepatic lipid peroxidation and cell death. Multi-omics analysis revealed that crizotinib induces Ferroptosis through processes such as Cholesterol metabolism, glutathione metabolism, Oxidative Phosphorylation, and iron ion transport. Notably, changes in RNA methylation levels may play a crucial role in the Ferroptosis triggered by crizotinib. Our findings highlight Ferroptosis as an important mechanism underlying crizotinib-induced liver injury, providing new insights into the adverse drug reaction mechanisms of crizotinib.

Crizotinib; Ferroptosis; Hepatoxicity; Metabolomics; Methylation; Transcriptomics.