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Updated: Sep 13, 2025
Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
Published on: January 31, 2022
Magnesium Isoglycyrrhizinate Alleviates Alectinib-Induced Hepatotoxicity by Inhibiting Mitochondrial Damage-Mediated
Yizhang Chen1,2, Chenxiang Wang1, Yuna Wu3
1Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
Introduction:
Alectinib is a widely used first-line ALK inhibitor for fusion-positive non-small cell lung cancer. However, its clinical use is limited by hepatotoxicity, and its mechanism remains unclear. This study aims to elucidate how alectinib induces liver injury and to explore a potential protective strategy.
Methods:
In vitro, AML-12 hepatocytes were incubated with alectinib to determine cell viability and morphology by using CCK-8 assay and optical microscopy, respectively. Necrosis was assessed by flow cytometry after Annexin V-FITC/PI staining. Mitochondrial damage was analyzed by measuring membrane potential, ultrastructure, and respiratory chain complex activities using JC-1 staining under fluorescence microscopy, transmission electron microscopy, and assay kits, respectively. Intracellular reactive oxygen species (ROS) levels were detected using DCFH-DA staining and flow cytometry. Pyroptosis- and oxidative stress-related proteins (NLRP3, GSDMD-N, P20, cleaved IL-1β, Nrf2, HO-1) were quantified by Western blot. In vivo, C57BL/6J mice were divided into control, alectinib treatment, and alectinib plus magnesium isoglycyrrhizinate (MgIG) treatment groups. Serum ALT and AST were measured to assess liver function. Hepatic oxidative stress was evaluated by SOD and MDA levels. Inflammatory cytokines including IL-1β and TNF-α were measured by corresponding kits. Liver histopathology was examined by hematoxylin-eosin staining.
Results:
We found alectinib could induce the death of AML-12 hepatocytes. Alectinib impaired both the function and structure of mitochondria and caused a significant increase in ROS levels. The excessive accumulation of ROS triggered oxidative stress and finally resulted in cell pyroptosis in AML-12 cells. MgIG was found to alleviate mitochondrial damage and reduce ROS levels, restore the Nrf2/HO-1 signaling pathway, thereby inhibiting oxidative stress and pyroptosis caused by alectinib.
Conclusion:
Alectinib induces elevated ROS levels in hepatocytes by damaging mitochondria and causing oxidative stress in hepatocytes, which results in cell pyroptosis and ultimately hepatotoxicity, whereas MgIG can treat alectinib-induced hepatic injury by restoring mitochondrial function and structure.
Insights
Alectinib causes liver injury by increasing reactive oxygen species (ROS) through mitochondrial damage, leading to cell pyroptosis. Magnesium isoglycyrrhizinate (MgIG) protects the liver by restoring mitochondrial function and reducing ROS.
Area of Science:
- Hepatology
- Oncology
- Pharmacology
Background:
- Alectinib is a key first-line treatment for ALK-positive non-small cell lung cancer.
- Hepatotoxicity is a significant limitation to alectinib's clinical application, with its underlying mechanisms requiring elucidation.
Purpose of the Study:
- To investigate the mechanism by which alectinib induces liver injury.
- To explore magnesium isoglycyrrhizinate (MgIG) as a potential protective agent against alectinib-induced hepatotoxicity.
Main Methods:
- In vitro studies utilized AML-12 hepatocytes to assess cell viability, mitochondrial function, reactive oxygen species (ROS) generation, and pyroptosis.
- In vivo studies in C57BL/6J mice evaluated liver function, oxidative stress markers, inflammatory cytokines, and histopathology following alectinib treatment with or without MgIG.
Main Results:
- Alectinib induced hepatocyte death, impaired mitochondrial function, and increased ROS levels, triggering oxidative stress and pyroptosis.
- MgIG treatment mitigated alectinib-induced mitochondrial damage and ROS accumulation, restoring the Nrf2/HO-1 signaling pathway and inhibiting pyroptosis.
Conclusions:
- Alectinib-induced hepatotoxicity stems from mitochondrial damage, elevated ROS, oxidative stress, and subsequent pyroptosis.
- MgIG demonstrates therapeutic potential by restoring mitochondrial integrity and function, thereby ameliorating alectinib-induced liver injury.
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