Magnesium isoglycyrrhizinate ameliorates ceritinib-induced hepatotoxicity by restoring mitochondrial homeostasis.

Ceritinib is a first-line drug for treating non-small cell lung cancer, but its clinical use is limited by severe hepatotoxicity. The mechanism underlying ceritinib-induced liver injury remains unclear. This study aimed to clarify this mechanism and evaluate the protective effect of magnesium isoglycyrrhizinate (MgIG). Hepatocytes were treated with ceritinib to assess cell viability and morphology using the CCK-8 assay and bright-field microscopy, respectively. Mitochondrial damage was evaluated by measuring membrane potential, ultrastructure, and NADH-CoQ reductase activity. Intracellular reactive oxygen species (ROS) levels were detected by DCFH-DA staining and flow cytometry. Western blotting was used to quantify oxidative stress- and pyroptosis-related proteins. Liver injury was assessed by serum ALT and AST levels and histopathological analysis. We found that ceritinib induced hepatocyte death by disrupting mitochondrial function and structure, leading to ROS accumulation, oxidative stress, NF-κB signaling activation and subsequent pyroptosis. MgIG treatment restored NADH-CoQ reductase activity, reduced ROS levels, and inhibited NF-κB activation, thereby attenuating oxidative stress and pyroptosis. These protective effects were confirmed in the animal model. In conclusion, ceritinib-induced hepatotoxicity is mediated by mitochondrial dysfunction, which triggers ROS-driven oxidative stress and pyroptosis. MgIG effectively mitigates this toxicity both in vitro and in vivo.