Falcarindiol alleviates airway inflammation and oxidative stress in asthma through Nrf2 pathway activation.

Oxidative stress and Th2-type immune responses play pivotal roles in asthma pathogenesis. Falcarindiol (FAD), a natural polyacetylene compound, exhibits promising anti-inflammatory and antioxidant properties, yet its therapeutic mechanism and efficacy in asthma treatment remain to be explored. An ovalbumin (OVA)-induced murine asthma model and IL-13-stimulated human bronchial epithelial cells (BEAS-2B) were employed to investigate FAD’s therapeutic mechanisms. Airway inflammation, oxidative stress markers, and Nrf2 pathway activation were comprehensively evaluated through hematoxylin and eosin (H&E) staining, ELISA, flow cytometry, and Western blotting. To establish mechanistic causality, the Nrf2 inhibitor ML385 and targeted shRNA knockdown approaches were used to validate the essential role of Nrf2 activation in mediating FAD’s protective effects. In OVA-induced asthmatic mice, FAD (100 or 200 mg/kg) produced dose-dependent therapeutic benefits, significantly reducing inflammatory scores, decreasing airway wall and smooth muscle thickness, substantially lowering serum IgE levels, and diminishing eosinophil infiltration in bronchoalveolar lavage fluid (BALF). Additionally, FAD effectively ameliorated oxidative stress, while simultaneously suppressing pro-inflammatory cytokine release. In IL-13-stimulated BEAS-2B cells, FAD dose-dependently protected against apoptosis and restored proliferation capacity while robustly activating the Nrf2/HO-1/NQO1 pathway. Mechanistic validation studies revealed that both ML385-mediated Nrf2 inhibition and Nrf2 shRNA knockdown largely abrogated FAD’s protective effects. FAD exerts anti-asthmatic effects through Nrf2 pathway activation, effectively mitigating airway inflammation, oxidative stress, and epithelial injury, establishing it as a promising therapeutic candidate for asthma.