Metabolic control of NETosis: dunnione suppresses inflammatory responses through NQO1–dependent redox modulation
7 affiliations
- 1Biomedical Science, Wonkwang University School of Medicine
- 2Center for Metabolic Function Regulation (CMFR) and Department of Microbiology, Wonkwang University School of Medicine
- 3NADIANBIO Ltd, Wonkwang University School of Medicine
- 4Department of Biochemistry & Molecular Biology, Institute of Medical Science, Jeonbuk National University Medical School
- 5Department of Biochemistry, Wonkwang University School of Medicine
- 6Sarcopenia Total Solution Center, Wonkwang University School of Medicine
- 7Institute of Wonkwang Medical Science, Wonkwang University
Abstract
Introduction: Neutrophil extracellular traps (NETs) are important effectors of innate immunity but can contribute to inflammatory pathology when dysregulated. Although reactive oxygen species (ROS) are known to promote NET formation, the metabolic mechanisms that regulate NETosis remain incompletely understood. Here, we investigated whether modulation of intracellular NAD⁺/NADH redox balance regulates NET formation and inflammatory responses.
Methods: Using primary neutrophils, differentiated HL-60 cells, and an imiquimod-induced psoriasis-like mouse model, we investigated the effects of dunnione, an NQO1 substrate, on NET formation and inflammatory responses.
Results: Dunnione significantly suppressed NET formation and inflammation. Dunnione increased the intracellular NAD⁺/NADH ratio in an NQO1-dependent manner and was accompanied by increased SIRT1 activity. This effect was associated with suppression of PAD4-mediated histone H3 citrullination and attenuation of NF-κB-dependent pro-inflammatory cytokine expression via deacetylation. In addition, dunnione reduced ROS generation and NOX2 activation, further limiting NET formation. The inhibitory effect of dunnione on NET formation was lost under NQO1-deficient conditions, indicating that NQO1 is required for dunnione responsiveness rather than for NET formation itself. In vivo , dunnione significantly attenuated psoriasis-like skin inflammation in association with reduced NET formation and inflammatory responses.
Discussion: Collectively, these findings support a metabolic mechanism in which NQO1-dependent redox modulation, accompanied by NAD ⁺ SIRT1-associated signaling, contributes to the suppression of NETosis and inflammatory responses.
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BibTeX
@article{zhu2026metabolic,
title = {{Metabolic control of NETosis: dunnione suppresses inflammatory responses through NQO1–dependent redox modulation}},
author = {Meng-Yu Zhu and Seung-Hoon Lee and Gi-Su Oh and Jong-Suk Kim and Jae Ho Seo and Hong-Seob So},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1973758},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1973758/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Metabolic control of NETosis: dunnione suppresses inflammatory responses through NQO1–dependent redox modulation
AU - Meng-Yu Zhu
AU - Seung-Hoon Lee
AU - Gi-Su Oh
AU - Jong-Suk Kim
AU - Jae Ho Seo
AU - Hong-Seob So
PY - 2026
DA - 2026/10/22
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1973758
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1973758/full
AB - Introduction: Neutrophil extracellular traps (NETs) are important effectors of innate immunity but can contribute to inflammatory pathology when dysregulated. Although reactive oxygen species (ROS) are known to promote NET formation, the metabolic mechanisms that regulate NETosis remain incompletely understood. Here, we investigated whether modulation of intracellular NAD⁺/NADH redox balance regulates NET formation and inflammatory responses. Methods: Using primary neutrophils, differentiated HL-60 cells, and an imiquimod-induced psoriasis-like mouse model, we investigated the effects of dunnione, an NQO1 substrate, on NET formation and inflammatory responses. Results: Dunnione significantly suppressed NET formation and inflammation. Dunnione increased the intracellular NAD⁺/NADH ratio in an NQO1-dependent manner and was accompanied by increased SIRT1 activity. This effect was associated with suppression of PAD4-mediated histone H3 citrullination and attenuation of NF-κB-dependent pro-inflammatory cytokine expression via deacetylation. In addition, dunnione reduced ROS generation and NOX2 activation, further limiting NET formation. The inhibitory effect of dunnione on NET formation was lost under NQO1-deficient conditions, indicating that NQO1 is required for dunnione responsiveness rather than for NET formation itself. In vivo , dunnione significantly attenuated psoriasis-like skin inflammation in association with reduced NET formation and inflammatory responses. Discussion: Collectively, these findings support a metabolic mechanism in which NQO1-dependent redox modulation, accompanied by NAD ⁺ SIRT1-associated signaling, contributes to the suppression of NETosis and inflammatory responses.
SN - 1664-3224
ER -