Arsenic trioxide preconditioning attenuates hepatic ischemia- reperfusion injury in mice: Role of ERK/AKT and autophagy

  • Chin Med J (Engl). 2025 Jan 17. doi: 10.1097/CM9.0000000000003411.
Chaoqun Wang  1  2 ,  Hongjun Yu  1 ,  Shounan Lu  1 ,  Shanjia Ke  1 ,  Yanan Xu  1 ,  Zhigang Feng  3 ,  Baolin Qian  1 ,  Miaoyu Bai  1 ,  Bing Yin  1 ,  Xinglong Li  1 ,  Yongliang Hua  4 ,  Zhongyu Li  1 ,  Dong Chen  1 ,  Bangliang Chen  1 ,  Yongzhi Zhou  1 ,  Shangha Pan  1 ,  Yao Fu  5 ,  Hongchi Jiang  6 ,  Dawei Wang  7 ,  Yong Ma  1
Affiliations
  • 1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimal Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China.
  • 2. Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China.
  • 3. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Department of General Surgery, The Affiliated Hospital of Inner Mongolia Minzu University, Tongliao, Inner Mongolia 028000, China.
  • 4. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Pediatric Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China.
  • 5. Department of Ultrasound, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China.
  • 6. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China.
  • 7. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Anorectal Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China.
PMID: 39820060 DOI: 10.1097/CM9.0000000000003411
Abstract

Background: Arsenic trioxide (ATO) is indicated as a broad-spectrum medicine for a variety of diseases, including Cancer and cardiac disease. While the role of ATO in hepatic ischemia/reperfusion injury (HIRI) has not been reported. Thus, the purpose of this study was to identify the effects of ATO on HIRI.

Methods: In the present study, we established a 70% hepatic warm I/R injury and partial hepatectomy (30% resection) animal models in vivo and hepatocytes anoxia/reoxygenation (A/R) models in vitro with ATO pretreatment and further assessed liver function by histopathologic changes, enzyme-linked immunosorbent assay, cell counting kit-8, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Small interfering RNA (siRNA) for extracellular signal-regulated kinase (ERK) 1/2 was transfected to evaluate the role of ERK1/2 pathway during HIRI, followed by ATO pretreatment. The dynamic process of autophagic flux and numbers of autophagosomes were detected by Green fluorescent protein-monomeric Red fluorescent protein-LC3 (GFP-mRFP-LC3) staining and transmission electron microscope.

Results: A low dose of ATO (0.75 μmol/L in vitro and 1 mg/kg in vivo) significantly reduced tissue necrosis, inflammatory infiltration, and hepatocyte Apoptosis during the process of hepatic I/R. Meanwhile, ATO obviously promoted the ability of cell proliferation and liver regeneration. Mechanistically, in vitro studies have shown that nontoxic concentrations of ATO can activate both ERK and phosphoinositide 3-kinase-serine/threonine kinase (PI3K-AKT) pathways and further induce Autophagy. The hepatoprotective mechanism of ATO, at least in part, relies on the effects of ATO on the activation of Autophagy, which is ERK-dependent.

Conclusion: Low, non-toxic doses of ATO can activate ERK/PI3K-AKT pathways and induce ERK-dependent Autophagy in hepatocytes, protecting liver against I/R injury and accelerating hepatocyte regeneration after partial hepatectomy.

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