Rosavin alleviates COPD via inhibition of IL-17-enriched NET formation and NF-κB signaling

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide and is characterized by persistent inflammation, microbiota dysbiosis, and excessive neutrophil extracellular trap (NET) formation. Rosavin, a natural phenylpropanoid glycoside, exhibits anti-inflammatory and immunomodulatory activities, but its therapeutic potential in COPD remains unclear.

A COPD rat model was induced by intratracheal lipopolysaccharide instillation combined with chronic passive cigarette smoke exposure. Rosavin (50 or 100 mg/kg) or the NF-κB inhibitor BAY 11-7082 (3 mg/kg) was administered for treatment. Pulmonary function tests (FEV1/FVC, PEF, and airway resistance), histopathological evaluation (HE and PAS staining), bronchoalveolar lavage fluid (BALF) inflammatory cell counts, ELISA-based cytokine assays, and oxidative stress markers (MDA, MPO, and SOD) were systematically assessed. NET formation was evaluated using MPO-DNA ELISA, Western blotting, and immunofluorescence for CitH3 and MPO/IL-17 colocalization. In addition, lung microbiota composition was analyzed by 16 S rRNA gene sequencing. Cigarette smoke extract (CSE)-stimulated BEAS-2B cells were used to assess the direct effects of Rosavin on NF-κB activation in vitro.

Rosavin significantly inhibited NF-κB activation, improved lung function, and reduced structural damage, oxidative stress, and inflammatory cytokines in COPD rats. It also suppressed NET formation, including IL-17-enriched NETs, by downregulating MPO, NE, and CitH3. In BEAS-2B cells, Rosavin similarly reduced CSE-induced NF-κB activation and cytokine release. Microbiota profiling showed decreased diversity and enrichment of Fusobacterium nucleatum in COPD rats, whereas Rosavin restored beneficial taxa such as Lactobacillus spp. BAY 11-7082 produced comparable effects, supporting NF-κB inhibition as a key mechanism.

Rosavin ameliorates COPD-associated pathology through integrated mechanisms involving NF-κB inhibition, reduction of IL-17-enriched NET formation, and modulation of lung microbiota composition. These findings identify Rosavin as a promising multi-target therapeutic candidate for COPD.