DNAJB4/HLJ1 protects against acetaminophen-induced liver injury by attenuating ER stress via HSP70
Journal
Cell Biology and Toxicology
Journal Volume
42
Journal Issue
1
Start Page
76
ISSN
1573-6822
Date Issued
2026-12
Author(s)
Lu, Chih-Yun
Hsieh, Tsung-Hsuan
Chien, Min-Hui
Hsu, Wei-Lun
Luo, Wei-Jia
Chang, Jung-Hsuan
Lee, Chia-I
Chen, Yi-Chun
Fang, Cheng-Hao
Abstract
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), Dnajb4exhibited 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.
Subjects
Acetaminophen
Acute liver failure
DNAJB4
Drug-induced liver injury
ER stress
Heat shock proteins
Type
journal article