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Published on: September 22, 2023
m6A-Related Regulation of Ferroptosis Contributes to Nasal Epithelial Barrier Dysfunction in Allergic Rhinitis
Zehua Lin1, Baoai Han1, Qiang Xie1
1Department of Otorhinolaryngology Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
Background:
Ferroptosis is a non-apoptotic form of cell death driven by lipid peroxidation. Although elevated lipid peroxidation has been linked to respiratory epithelial injury, its role in allergic rhinitis (AR) remains unclear. Therefore, in this study, we aimed to assess the role of ferroptosis in AR pathogenesis and elucidate its molecular mechanism.
Methods:
Human nasal epithelial cells (HNEpC and RPMI-2650) and Balb/c mice were used to evaluate house dust mite (HDM)-induced ferroptosis related responses and nasal epithelial barrier disruption. Clinical nasal mucosal samples were collected to validate key experimental findings. N6-methyladenosine (m6A) methylation levels were assessed by m6A assays and dot blot analysis, predicted m6A sites were identified using SRAMP, and RIP-qPCR and MeRIP-qPCR were performed to examine RNA-protein interactions and site-specific m6A enrichment, respectively.
Results:
HDM exposure induced lipid peroxidation-driven ferroptosis-related epithelial barrier disruption. Glutathione peroxidase 4 (GPX4) acted as a protective regulator, as ferroptosis inhibition or GPX4 overexpression alleviated epithelial damage. Growth arrest-specific 1 (GAS1) promoted ferroptosis by suppressing GPX4 expression, a finding further supported by in vivo validation in GAS1-knockdown mice. Mechanistically, this GAS1-GPX4 regulatory relationship was linked to METTL3-mediated m6A modification of GPX4 mRNA at the site 625.
Conclusions:
These findings suggest a novel mechanism whereby HDM exposure promotes ferroptosis-related nasal epithelial barrier impairment through GAS1-METTL3-mediated regulation of GPX4 m6A methylation, thereby contributing to AR pathogenesis.
Insights
House dust mite exposure triggers ferroptosis, a cell death pathway, leading to nasal epithelial barrier damage in allergic rhinitis. This damage is mediated by GAS1 suppressing GPX4, a process regulated by m6A methylation.
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.
