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CN 22-1108/R
Volume 42 Issue 1
Jan.  2026
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Article Navigation >  Journal of Clinical Hepatology  > 2026  >  42(1): 134-142

Role of endoplasmic reticulum stress-mediated DEAD-box helicase 3 X-linked in a mouse model of concanavalin A-induced immune-mediated liver injury

DOI: 10.12449/JCH260116

  • Institute of Hepatology，Beijing YouAn Hospital，Capital Medical University，Beijing 100069，China

Research funding:

National Natural Science Foundation of China (81770611);

National Natural Science Foundation of China (82002243);

Key Projects of the Beijing Municipal Education Commission’s Science and Technology Plan (KZ202010025035);

Special Key Research Project of Capital Health Development Scientific Research (SF2020-1-1151);

The Demonstrating Application and Research of Clinical Diagnosis and Treatment Technology in Beijing (Z191100006619096);

The Demonstrating Application and Research of Clinical Diagnosis and Treatment Technology in Beijing (Z191100006619097);

Beijing Hospitals Authority Youth Programme (QML20201702);

Talent Cultivation plan of “Climbing the Peak” of Beijing Municipal Hospital Administration (DFL20221503);

High-level Public Health Technical Personnel Construction Project (Subject leaders-02-13)

More Information
  • Corresponding author: REN Feng， renfeng7512@ccmu.edu.cn （ORCID： 0000-0001-7736-8637）
  • Received Date: 2025-06-22
  • Accepted Date: 2025-09-18
  • Published Date: 2026-01-25
    Abstract
  •   Objective  To investigate the role of DEAD-box helicase 3 X-linked （DDX3X） in immune-mediated liver injury （ILI）， and to clarify its mechanism by regulating endoplasmic reticulum stress （ERS）-dependent apoptotic pathway and its association with the clinical progression of hepatitis B.  Methods  Mice were given injection of concanavalin A （ConA） via the caudal vein to establish a model of ILI， PBS （control group） and different concentrations of ConA were injected into the tail vein of hepatocyte-specific DDX3X-knockout mice （DDX3XΔHep and DDX3X-flox mice （DDX3Xfl/fl）， respectively.. The log-rank survival analysis， measurement of the serum levels of aspartate aminotransferase （AST） and alanine aminotransferase （ALT）， and HE staining of liver tissue were performed to assess liver injury， and qRT-PCR and Western Blot were used to measure the mRNA and protein expression levels of glucose-regulated protein 78 （GRP78）， CCAAT/enhancer-binding protein homologous protein （CHOP）， and DDX3X in liver tissue. Intraperitoneal injection of 4-phenylbutyric acid （4-PBA， 100 mg/kg） was performed to inhibit ERS. Serum samples （n=30） and liver tissue samples （n=6） were collected from healthy controls， chronic hepatitis B （CHB） patients， and hepatitis B virus-associated liver failure （HBV-LF） patients； ELISA was used to measure the serum level of DDX3X， and qRT-PCR/Western Blot was used to analyze the expression of targets in liver tissue. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups.  Results  Compared with the control group of mice， the expression of DDX3X in the liver of mice induced by ConA was significantly increased after liver injury （P<0.05）， and hepatocyte-specific DDX3X knockout increased the 72-hour survival rate of mice by 55% （compared with 20% in the DDX3Xfl/fl group）， with significant reductions in the serum levels of ALT and AST （P<0.000 1） and the expression levels of the ERS markers GRP78 and CHOP （P<0.05）. After ERS was inhibited by 4-PBA， there was alleviation of liver injury （with reductions in ALT and AST， P <0.001） and a reduction in DDX3X expression （P<0.01）. The analysis of clinical samples showed that the mRNA and protein expression levels of liver DDX3X in CHB patients and HBV-LF patients were significantly higher than those in healthy controls （all P<0.01）， and there was a significant increase in the serum level of DDX3X in HBV-LF patients （P<0.000 1）.  Conclusion  DDX3X exacerbates ILI by regulating the ERS-dependent apoptotic pathway （GRP78/CHOP）， and its expression is associated with the progression of hepatitis B. Therefore， it can be used as a potential therapeutic target.

     

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