NQO1 acts as a context-dependent regulator of oxidative stress and biliary fibrosis in primary sclerosing cholangitis
- 1Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- 2Department of Biology and Microbiology, Changwon National University, Changwon, Korea
Abstract
Background
Primary sclerosing cholangitis (PSC) remains a challenging biliary disease characterized by persistent inflammation and extensive fibrosis. However, its molecular drivers are not fully understood. Here, we explored the functional significance of NAD(P)H:quinone oxidoreductase 1 (NQO1) in the progression of PSC.Methods
Wild-type (WT) and Nqo1 knockout (NKO) male mice were fed a diet containing 0.1% (w/w) 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 1 or 3 weeks to induce cholestatic liver injury. Liver tissues and plasma samples were collected for biochemical, histological, and molecular analyses. To further investigate the underlying mechanisms, in vitro experiments were performed using HepG2 and LX-2 cell lines as well as primary hepatocytes.Results
NQO1 expression was markedly upregulated under cholestatic conditions. During the acute phase of DDC-induced injury, NKO mice demonstrated a protective phenotype, characterized by significantly reduced plasma ALT levels and less severe histological injury compared with WT controls. Histological analysis further revealed fewer TUNEL-positive hepatocytes and reduced fibrotic deposition in NKO mice. Transcriptomic profiling indicated that NQO1 ablation suppressed the epithelial-mesenchymal transition (EMT) and inflammation pathways, while enhancing bile acids and xenobiotic metabolism. Mechanistically, periostin was identified as a key upstream factor capable of inducing NQO1 expression and promoting intracellular reactive oxygen species (ROS) accumulation. Periostin-induced NQO1 protein expression was attenuated by both BAY 11-7082 and N-acetyl-L-cysteine. Notably, the disruption of NQO1 blunted periostin-driven oxidative stress. However, this protective effect is limited to the early phase of the disease and is not maintained during prolonged cholestatic injury.Conclusion
NQO1 can function as a context-dependent regulator that exacerbates oxidative stress and fibrosis during the initial stages of PSC and suggests that targeting the periostin-NQO1 axis may offer therapeutic benefits.
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BibTeX
@article{kim2026nqo1,
title = {{NQO1 acts as a context-dependent regulator of oxidative stress and biliary fibrosis in primary sclerosing cholangitis}},
author = {Juhyun Kim and Seung Hee Woo and Da-Hyeun Yoon and Heedoo Lee and Chul-Ho Lee and Jung Hwan Hwang},
journal = {Hepatology communications},
year = {2026},
month = oct,
doi = {10.1097/hc9.0000000000001076},
url = {https://europepmc.org/article/PMC/PMC13694090},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - NQO1 acts as a context-dependent regulator of oxidative stress and biliary fibrosis in primary sclerosing cholangitis
AU - Juhyun Kim
AU - Seung Hee Woo
AU - Da-Hyeun Yoon
AU - Heedoo Lee
AU - Chul-Ho Lee
AU - Jung Hwan Hwang
PY - 2026
DA - 2026/10/23
JO - Hepatology communications
DO - 10.1097/hc9.0000000000001076
UR - https://europepmc.org/article/PMC/PMC13694090
AB - Background Primary sclerosing cholangitis (PSC) remains a challenging biliary disease characterized by persistent inflammation and extensive fibrosis. However, its molecular drivers are not fully understood. Here, we explored the functional significance of NAD(P)H:quinone oxidoreductase 1 (NQO1) in the progression of PSC.Methods Wild-type (WT) and Nqo1 knockout (NKO) male mice were fed a diet containing 0.1% (w/w) 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 1 or 3 weeks to induce cholestatic liver injury. Liver tissues and plasma samples were collected for biochemical, histological, and molecular analyses. To further investigate the underlying mechanisms, in vitro experiments were performed using HepG2 and LX-2 cell lines as well as primary hepatocytes.Results NQO1 expression was markedly upregulated under cholestatic conditions. During the acute phase of DDC-induced injury, NKO mice demonstrated a protective phenotype, characterized by significantly reduced plasma ALT levels and less severe histological injury compared with WT controls. Histological analysis further revealed fewer TUNEL-positive hepatocytes and reduced fibrotic deposition in NKO mice. Transcriptomic profiling indicated that NQO1 ablation suppressed the epithelial-mesenchymal transition (EMT) and inflammation pathways, while enhancing bile acids and xenobiotic metabolism. Mechanistically, periostin was identified as a key upstream factor capable of inducing NQO1 expression and promoting intracellular reactive oxygen species (ROS) accumulation. Periostin-induced NQO1 protein expression was attenuated by both BAY 11-7082 and N-acetyl-L-cysteine. Notably, the disruption of NQO1 blunted periostin-driven oxidative stress. However, this protective effect is limited to the early phase of the disease and is not maintained during prolonged cholestatic injury.Conclusion NQO1 can function as a context-dependent regulator that exacerbates oxidative stress and fibrosis during the initial stages of PSC and suggests that targeting the periostin-NQO1 axis may offer therapeutic benefits.
SN - 2471-254X
ER -