Upregulation of PTEN mediated by FTO-m6A-YTHDF2 improves airway epithelial barrier damage and inflammation in asthma by inhibiting endoplasmic reticulum stress.

Phosphatase and tensin homolog deleted on chromosome ten (PTEN) alleviates airway remodeling in asthmatic mice by inhibiting CD38 protein expression. Dysregulation of PTEN expression mediated by N6-methyladenosine (m6A) regulators is involved in the progression of a variety of diseases. However, whether the dysregulated expression of PTEN in asthma is regulated by m6A modification remains unclear. Here, we constructed an asthma cell model by stimulating bronchial epithelial cells with house dust mite (HDM) and found that PTEN expression was downregulated in HDM-stimulated HBE135-E6E7 cells. PTEN overexpression promoted cell proliferation, reduced cell membrane permeability and inflammatory factor levels, increased trans-epithelial electrical resistance (TEER) and junction protein levels, and inhibited cell apoptosis in HDM-stimulated HBE135-E6E7 cells. Mechanistic studies revealed that fat mass and obesity-associated gene (FTO) upregulated PTEN expression by reducing m6A-YTH m6A RNA-binding protein 2 (YTHDF2)-mediated PTEN mRNA degradation. Upregulated PTEN inhibited CD38 protein expression, and overexpression of CD38 activated the IRE1β-RACK1 pathway by interacting with inositol-requiring enzyme 1beta (IRE1β) to enhance endoplasmic reticulum (ER) stress, promoting inflammation and barrier damage in HBE135-E6E7 cells. Finally, an asthma mouse model was constructed by HDM stimulation, and adenovirus of FTO knockdown or overexpression of YTHDF2 or PTEN were injected into asthmatic mice. The results showed that the FTO/m6A/YTHDF2 axis mediated PTEN upregulation alleviated airway inflammation and epithelial barrier damage in HDM-induced asthmatic mice. In conclusion, FTO-m6A-YTHDF2 mediated PTEN upregulation inhibits ER stress by blocking the CD38/IRE1β-RACK1 pathway, alleviating airway inflammation and epithelial barrier damage in asthma.