Work

Metabolic control of NETosis: dunnione suppresses inflammatory responses through NQO1–dependent redox modulation

Year: 2026

Type: article

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.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2026.1973758

Authors: Meng-Yu Zhu, Seung-Hoon Lee, Gi-Su Oh, Jong-Suk Kim, Jae Ho Seo, Hong-Seob So

Institutions: Wonkwang University, Jeonbuk National University

Language: English

Topic: Neutrophil, Myeloperoxidase and Oxidative Mechanisms

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801