m6A-Related Regulation of Ferroptosis Contributes to Nasal Epithelial Barrier Dysfunction in Allergic Rhinitis

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Ferroptosis, a cell death form driven by lipid peroxidation, is implicated in respiratory injury but its role in allergic rhinitis (AR) is unknown.
• Investigating ferroptosis in AR is crucial for understanding disease pathogenesis.

Purpose of the Study:

• To assess the role of ferroptosis in allergic rhinitis (AR) pathogenesis.
• To elucidate the molecular mechanisms underlying ferroptosis in AR.

Main Methods:

• Utilized human nasal epithelial cells and mouse models to study house dust mite (HDM)-induced ferroptosis and barrier disruption.
• Employed m6A assays, RIP-qPCR, and MeRIP-qPCR to analyze N6-methyladenosine (m6A) methylation and its regulatory role.
• Validated findings using clinical nasal mucosal samples and GAS1-knockdown mice.

Main Results:

• HDM exposure induced ferroptosis and epithelial barrier disruption, characterized by increased lipid peroxidation.
• Glutathione peroxidase 4 (GPX4) protected against ferroptosis; its inhibition or knockdown exacerbated epithelial damage.
• Growth arrest-specific 1 (GAS1) promoted ferroptosis by downregulating GPX4, a mechanism confirmed in vivo.
• GAS1's effect on GPX4 was mediated by METTL3-dependent m6A modification of GPX4 mRNA.

Conclusions:

• HDM exposure drives AR pathogenesis via ferroptosis-induced nasal epithelial barrier impairment.
• GAS1-METTL3-mediated regulation of GPX4 m6A methylation represents a novel mechanism in AR.
• Targeting this pathway may offer therapeutic strategies for allergic rhinitis.