Natural Flavonoid Nobiletin Attenuates Allergic Asthma via Suppression of STAT3 / PI3K ‐ AKT and Neutrophil Extracellular Traps

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Allergic asthma is classically defined by eosinophilic inflammation and Th2 immune responses. However, neutrophils are increasingly recognized as key contributors, particularly through the release of neutrophil extracellular traps (NETs), which exacerbate airway inflammation by promoting antigen presentation and amplifying Th2 responses. Recent studies have identified an immunoglobulin E (IgE)-nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2)-reactive oxygen species (ROS)-nitric oxide (NO)-myeloperoxidase (MPO) axis as a critical NET-inducing pathway, independent of inducible nitric oxide synthase (iNOS). This study investigated whether nobiletin, a citrus-derived polymethoxyflavonoid, attenuates allergic airway inflammation by targeting NET formation. Using an ovalbumin (OVA)-induced murine model of asthma, we assessed the effects of nobiletin on airway pathology, immune cell infiltration, cytokine expression, and signaling pathway activity through multiple cellular and molecular assays. Nobiletin treatment significantly reduced airway inflammation, mucus hypersecretion, and collagen deposition, while it decreased eosinophil and neutrophil accumulation in bronchoalveolar lavage fluid and lung tissue. It also suppressed Th2 cytokines (IL-4, IL-5, IL-13) and proinflammatory mediators (IL-6, IL-17A, TNF-α). Mechanistically, nobiletin inhibited NET formation by blocking PI3K/AKT and STAT3 signaling, with molecular docking confirming its binding to both targets. These findings identify nobiletin as a promising dual-target therapeutic agent that concurrently modulates Th2-driven and neutrophil-mediated inflammation in allergic asthma.

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