METTL3-mediated m6A modification of circCDKAL1 regulates macrophage M1 polarization and nasal epithelial cell barrier function in allergic rhinitis through IGF2BP2/JARID2/HMGB1 axis

Jiabin Zhan; Dan Luo; Yunlong Fu; Yu Zhou; Rui Li; Xin Wei

doi:10.1038/s41420-025-02710-7

METTL3-mediated m6A modification of circCDKAL1 regulates macrophage M1 polarization and nasal epithelial cell barrier function in allergic rhinitis through IGF2BP2/JARID2/HMGB1 axis

Cell Death Discov. 2025 Aug 29;11(1):417. doi: 10.1038/s41420-025-02710-7.

Authors

Jiabin Zhan^#¹, Dan Luo^#¹, Yunlong Fu¹, Yu Zhou¹, Rui Li¹, Xin Wei²

Affiliations

¹ Department of Otorhinolaryngology Head and Neck Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou City, Hainan Province, PR China.
² Department of Otorhinolaryngology Head and Neck Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou City, Hainan Province, PR China. hnweking@sina.com.

^# Contributed equally.

Abstract

Allergic rhinitis (AR) is a chronic inflammatory disease that significantly impairs patients' quality of life, with CircCDKAL1 showing abnormal upregulation in AR patients, though its functional mechanisms remain unclear. In this study, we confirmed the identity of circCDKAL1 and its subcellular localization. Our findings revealed that circCDKAL1 expression was enhanced in samples of AR patients, AR mice and OVA-induced HNEpCs. Besides, circCDKAL1 silencing resulted in improvement of nasal mucosal epithelial barrier function/epithelial cell adhesion and promotion of macrophage M2 polarization in AR. Mechanistically, we discovered that circCDKAL1 was modified by m6A, which was mediated by METTL3. YTHDC1 promoted cytoplasmic output of m6A-modified circCDKAL1. In addition, circCDKAL1 destabilized JARID2 mRNA through interacting with IGF2BP2. Moreover, circCDKAL1 or HMGB1 silencing attenuated JARID2 silencing-mediated damages of epithelial cell adhesion and promotion of macrophage M1 polarization in OVA-induced HNEpCs. In conclusion, METTL3-mediated m6A modification of circCDKAL1, which was transferred from the nucleus to the cytoplasm by YTHDC1, promoted macrophage M1 polarization and impaired nasal mucosal epithelial barrier function/epithelial cell adhesion in AR through interacting with IGF2BP2 and regulating JARID2/HMGB1 axis.