2. Academic Validation
  3. Monocrotaline induces liver injury via TRX1-ASK1-JNK Axis-mediated mitochondrial damage in hepatocytes

Monocrotaline induces liver injury via TRX1-ASK1-JNK Axis-mediated mitochondrial damage in hepatocytes

  • Int Immunopharmacol. 2026 Mar 1:172:116121. doi: 10.1016/j.intimp.2025.116121.
Caixia Xia 1,  Yelei Cen 2,  Shouhan Yao 2,  Siduo Xu 2,  Guohua Lou 3,  Yanning Liu 4,  Min Zheng 5
Affiliations

Affiliations

  • 1 The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, China-Singapore Belt and Road Joint Laboratory on Infection Research and Drug Development, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China.; Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, China; Yuhang Institute for Collaborative Innovation and Translational Research in Life Sciences and Technology, Hangzhou 310003, Zhejiang, China.
  • 2 The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, China-Singapore Belt and Road Joint Laboratory on Infection Research and Drug Development, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China.; Yuhang Institute for Collaborative Innovation and Translational Research in Life Sciences and Technology, Hangzhou 310003, Zhejiang, China.
  • 3 The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, China-Singapore Belt and Road Joint Laboratory on Infection Research and Drug Development, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China.; Yuhang Institute for Collaborative Innovation and Translational Research in Life Sciences and Technology, Hangzhou 310003, Zhejiang, China.. Electronic address: [email protected].
  • 4 The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, China-Singapore Belt and Road Joint Laboratory on Infection Research and Drug Development, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China.; Yuhang Institute for Collaborative Innovation and Translational Research in Life Sciences and Technology, Hangzhou 310003, Zhejiang, China.. Electronic address: [email protected].
  • 5 The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, China-Singapore Belt and Road Joint Laboratory on Infection Research and Drug Development, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China.; Yuhang Institute for Collaborative Innovation and Translational Research in Life Sciences and Technology, Hangzhou 310003, Zhejiang, China.. Electronic address: [email protected].
PMID: 41519004 DOI: 10.1016/j.intimp.2025.116121
Abstract

Pyrrolizidine alkaloid-induced liver injury (PAs-ILI) is a significant hepatic disorder resulting from exposure to Pyrrolizidine Alkaloids (PAs), often presenting as acute liver damage that may progress to cirrhosis, liver failure, or death; however, its underlying mechanisms remain incompletely elucidated. This study employed monocrotaline (MCT), a well-established PA, to investigate the pathogenesis of PAs-ILI in a mouse model. Utilizing RNA-seq, Western blot, ROS detection, mitochondrial membrane potential and ATP assays, GSH quantification, transmission electron microscopy, and qRT-PCR, we demonstrated that MCT induced marked liver injury, as indicated by elevated serum biomarkers and histopathological changes. MCT provoked hepatic oxidative stress, characterized by increased ROS and significant suppression of thioredoxin 1 (TRX1), leading to mitochondrial dysfunction evidenced by reduced ATP production, membrane potential depolarization, and activation of the ASK1-JNK pro-apoptotic pathway. In vitro experiments in HepG2 cells confirmed MCT-induced DNA damage and ASK1-dependent JNK phosphorylation, underscoring the central role of this pathway in cytotoxicity. Pretreatment with the ASK1 Inhibitor Selonsertib (SEL) attenuated MCT-induced liver injury by suppressing ASK1-JNK activation and preserving mitochondrial integrity. These results indicate that MCT elicits hepatotoxicity via TRX1-ASK1-JNK axis-mediated mitochondrial damage, and that SEL disrupts this cascade, highlighting the therapeutic potential of ASK1 inhibition in PAs-ILI.

Keywords

ASK1; Hepatotoxicity; Mitochondrial damage; Monocrotaline (MCT); Oxidative stress; TRX1.

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