ITGA5 as a Dual Regulator of Epithelial‐Mesenchymal Transition and Epithelial Cell Anoikis Resistance: Functional Validation and Drug Prediction

Airway remodelling is a major contributor to persistent airflow limitation and irreversible lung function impairment in asthma, with epithelial-mesenchymal transition (EMT) serving as a key driver. However, the molecular mechanisms controlling EMT in asthma epithelium remain incompletely elucidated. This study reported that integrin α5 (ITGA5) was markedly upregulated in asthma patients, house dust mite (HDM)-sensitised asthma mice, and transforming growth factor beta 1 (TGF-β1)-induced in vitro EMT models. Elevated ITGA5 expression correlated positively with reduced lung function, asthma severity and higher levels of EMT regulators (Fibronectin, N-cadherin, Vimentin) and was functionally linked to anoikis resistance. In TGF-β1-induced bronchial epithelial cells exhibiting anoikis resistance, quantitative proteomics revealed that ITGA5 promoted mesenchymal transition via the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway and negatively regulated anoikis. ITGA5 directly bound to PI3K in vitro, and ITGA5 knockdown reversed TGF-β1-induced EMT, inhibited the activation of the PI3K/Akt pro-survival pathway, and restored anoikis sensitivity. According to molecular docking, molecular dynamics simulation and in vivo and in vitro pharmacological assays, resveratrol (Res) and M200 were found to be potential ITGA5 inhibitors that successfully reduced EMT and anoikis resistance, thereby attenuating airway remodelling in asthma mice and offering promising drug candidates for ITGA5-targeted therapy.