Abstract: Objective To explore the contribution of ferroptosis to airway remodeling in asthma by establishing a ovalbumin(OVA)-induced asthma mice model, and to provide new directions in the treatment of airway remodeling of asthma. Methods Twenty-four female C57BL/6 mice were stochastically divided into four groups: the control group(n=6), the OVA group(n=6), the ferrostatin(Fer)-1 group(n=6), and the Fer-1+OVA group(n=6). The association between ferroptosis and asthma was clarified by establishing the differentially expressed genes of lung tissues in the OVA-induced asthma mice and controls screened from public databases. The iron concentration was measured by iron detection kit and Perls stain, and the expression of glutathione peroxidase 4(GPX4)protein was evaluated by Western blotting and immunohistochemical staining. The levels of the lipid peroxidation product malondialdehyde(MDA)in lung tissue were assayed and the ultra-structural changes in the airway epithelium were observed using transmission electron microscopy(TEM). Lung tissue slices were stained with Masson staining to evaluate collagen deposition. To further verify the effect of ferroptosis inhibitor on the airway remodeling in asthma, the mice were intervened with Fer-1, and then collagen deposition was evaluated by MASSON staining, the expression of GPX4 protein was detected by immunofluorescence and Western blotting. Results The results of bioinformatics analysis showed that the ferroptosis signaling pathway was significantly enriched in OVA group, suggesting that ferroptosis played a certain role in the pathogenesis of asthma. Meanwhile, in this gene set, GPX4 was significantly decreased in OVA group. In asthma mice model, collagen deposition was accompanied by a series of ferroptosis features such as increased iron concentration, decreased GPX4 expression, MDA accumulation, increased collagen deposition, and characteristic ultra-structural changes in the airway epithelium, suggesting that ferroptosis was intimately linked with asthma airway remodeling. After treated with Fer-1, for the asthma model mice, the GPX4 expression was elevated, the collagen deposition was reducted, the expressions of airway remodeling indicators were suppressed, and epithelial cell markers were increased. Conclusion Ferroptosis participates in the pathogenesis of asthma airway remodeling, ferroptosis inhibitor Fer-1 attenuates airway remodeling in asthma, and the application of Fer-1 provides a new therapeutic target for asthmatic airway remodeling.

Key words: Asthma, Airway remodeling, Ferroptosis, Ferrostatin-1, Therapeutic target