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<p>Drug-induced liver injury (DILI) remains a leading cause of acute liver failure; however, current clinical strategies lack reliable biomarkers, predictors of susceptibility, and effective therapeutic interventions. Among these etiologies, acetaminophen (APAP) overdose is the most common cause of DILI worldwide. Heat shock proteins (HSPs), particularly members of the HSP40 family, are central regulators of cellular stress responses, yet the specific role of DNAJB4/HLJ1 in APAP-induced hepatotoxicity remains poorly defined. To address this gap, we employed DNAJB4/HLJ1-deficient mice (<i>Dnajb4</i><sup>−/−</sup>) to investigate the function of DNAJB4/HLJ1 in APAP-induced liver injury. Following APAP administration (&gt; 400&#xa0;mg/kg), <i>Dnajb4</i><sup>−/−&#xa0;</sup>exhibited exacerbated hepatic necrosis, elevated liver enzymes, and enhanced c-jun/JNK activation compared with <i>Dnajb4</i><sup>+/+</sup> controls. Metabolic profiling revealed altered APAP metabolism, with reduced detoxification products and excessive oxidative metabolites, and pronounced glutathione (GSH) depletion. Transcriptomic analysis implicated DNAJB4/HLJ1 in metabolism, protein folding, and endoplasmic reticulum (ER) stress via interaction with HSP70. Consistently, ATF6, XBP1, and CHOP expression confirmed aggravated ER stress in <i>Dnajb4</i><sup>−/−</sup> livers. AlphaFold-Multimer modeling and co-immunoprecipitation validated physical interaction between DNAJB4/HLJ1 and HSP70. Restoration of DNAJB4/HLJ1 expression attenuated ER stress, c-jun/JNK activation, and liver injury, while pharmacological inhibition of ER stress confirmed its mechanistic involvement. Collectively, these findings identify DNAJB4/HLJ1 as a previously unrecognized regulator of stress signaling in APAP-induced hepatotoxicity. By modulating ER stress within the integrated cellular stress network, DNAJB4/HLJ1 limits injury progression and promotes hepatocellular resilience, highlighting its potential as a novel therapeutic target for preventing or mitigating DILI.</p> Graphical Abstract <p>1. DNAJB4/HLJ1 acts as a critical safeguard against acetaminophen-induced liver njury.</p> <p>2. Its loss rewires APAP metabolism, driving toxic NAPQI accumulation and GSH collapse.</p> <p>3. DNAJB4/HLJ1 partners with HSP70 to restrain ER stress and halt JNK-driven damage.</p> <p>4. Reinstating DNAJB4/HLJ1 restores cellular resilience, revealing a targetable defense in drug-induced liver injury (DILI).</p> <p></p>

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DNAJB4/HLJ1 protects against acetaminophen-induced liver injury by attenuating ER stress via HSP70

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月1日

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  • Chih-Yun Lu,
  • Tsung-Hsuan Hsieh,
  • Min-Hui Chien,
  • Wei-Lun Hsu,
  • Wei-Jia Luo,
  • Jung-Hsuan Chang,
  • Chia-I Lee,
  • Yi-Chun Chen,
  • Cheng-Hao Fang,
  • Ching-Hua Kuo,
  • Sung-Liang Yu,
  • Kang-Yi Su

摘要

Drug-induced liver injury (DILI) remains a leading cause of acute liver failure; however, current clinical strategies lack reliable biomarkers, predictors of susceptibility, and effective therapeutic interventions. Among these etiologies, acetaminophen (APAP) overdose is the most common cause of DILI worldwide. Heat shock proteins (HSPs), particularly members of the HSP40 family, are central regulators of cellular stress responses, yet the specific role of DNAJB4/HLJ1 in APAP-induced hepatotoxicity remains poorly defined. To address this gap, we employed DNAJB4/HLJ1-deficient mice (Dnajb4−/−) to investigate the function of DNAJB4/HLJ1 in APAP-induced liver injury. Following APAP administration (> 400 mg/kg), Dnajb4−/− exhibited exacerbated hepatic necrosis, elevated liver enzymes, and enhanced c-jun/JNK activation compared with Dnajb4+/+ controls. Metabolic profiling revealed altered APAP metabolism, with reduced detoxification products and excessive oxidative metabolites, and pronounced glutathione (GSH) depletion. Transcriptomic analysis implicated DNAJB4/HLJ1 in metabolism, protein folding, and endoplasmic reticulum (ER) stress via interaction with HSP70. Consistently, ATF6, XBP1, and CHOP expression confirmed aggravated ER stress in Dnajb4−/− livers. AlphaFold-Multimer modeling and co-immunoprecipitation validated physical interaction between DNAJB4/HLJ1 and HSP70. Restoration of DNAJB4/HLJ1 expression attenuated ER stress, c-jun/JNK activation, and liver injury, while pharmacological inhibition of ER stress confirmed its mechanistic involvement. Collectively, these findings identify DNAJB4/HLJ1 as a previously unrecognized regulator of stress signaling in APAP-induced hepatotoxicity. By modulating ER stress within the integrated cellular stress network, DNAJB4/HLJ1 limits injury progression and promotes hepatocellular resilience, highlighting its potential as a novel therapeutic target for preventing or mitigating DILI.

Graphical Abstract

1. DNAJB4/HLJ1 acts as a critical safeguard against acetaminophen-induced liver njury.

2. Its loss rewires APAP metabolism, driving toxic NAPQI accumulation and GSH collapse.

3. DNAJB4/HLJ1 partners with HSP70 to restrain ER stress and halt JNK-driven damage.

4. Reinstating DNAJB4/HLJ1 restores cellular resilience, revealing a targetable defense in drug-induced liver injury (DILI).