YTHDF2 promotes ferroptosis of BECs in neutrophilic asthma and induces Th17 cell differentiation by regulating CYP19A1 m6A modification

The core pathological feature of neutrophilic asthma (NA) involves elevated secretion of Th1/Th17 cytokines. Ferroptosis of bronchial epithelial cells (BECs) is closely associated with NA pathogenesis, but its underlying mechanism remains unclear. This study aims to investigate how YTHDF2 regulates BEC ferroptosis and Th17 cell differentiation via CYP19A1 m 6 A methylation. A NA mouse model was established using house dust mite (HDM). An inflammatory model in BECs was constructed by co-stimulation with HDM and LPS. To investigate the role of the YTHDF2/CYP19A1/androgen receptor (AR)/GPX4 axis in regulating BEC ferroptosis and Th17 cell differentiation, interventions were performed using YTHDF2/CYP19A1/AR knockdown, the AR activator Dihydrotestosterone, AR inhibitor Flutamide, or GPX4 inhibitor RSL3. YTHDF2 was abnormally upregulated in NA model mice. YTHDF2 knockdown reduced the m 6 A methylation level and increased AR expression in HDM/LPS-treated BECs. AR activated GPX4 transcription to inhibit HDM/LPS-stimulated BEC ferroptosis and Th17 cell differentiation. YTHDF2 knockdown inhibited ferroptosis in HDM/LPS-stimulated BECs and Th17 cell differentiation by activating the AR/GPX4 axis. Mechanistically, YTHDF2 knockdown enhanced the CYP19A1 mRNA stability by reducing its m 6 A modification. CYP19A1 silencing reversed the protective effect of YTHDF2 knockdown on HDM/LPS-stimulated BECs. Notably, DHT treatment counteracted the detrimental impact of CYP19A1 deficiency on HDM/LPS-stimulated BECs. Our results indicate that YTHDF2 knockdown reduces the m 6 A modification of CYP19A1, enhances its mRNA stability. The upregulated CYP19A1 activates the AR pathway, promotes the transcriptional expression of GPX4, and ultimately inhibits ferroptosis in HDM/LPS-treated BECs and reduces Th17 cell differentiation. Our findings might provide candidate targets worthy of further validation in clinical samples for the study of human asthma.