Zhan Jiabin, Luo Dan, Fu Yunlong, Zhou Yu, Li Rui, Wei Xin
Department of Otorhinolaryngology Head and Neck Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou City, Hainan Province, PR China.
Cell Death Discov. 2025 Aug 29;11(1):417. doi: 10.1038/s41420-025-02710-7.
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.
变应性鼻炎（AR）是一种严重损害患者生活质量的慢性炎症性疾病，环状细胞周期蛋白依赖性激酶调节亚基相关蛋白1（CircCDKAL1）在AR患者中呈现异常上调，但其功能机制尚不清楚。在本研究中，我们证实了CircCDKAL1的特性及其亚细胞定位。我们的研究结果显示，CircCDKAL1在AR患者、AR小鼠和卵清蛋白诱导的人鼻黏膜上皮细胞（HNEpCs）样本中的表达增强。此外，CircCDKAL1沉默可改善AR患者鼻黏膜上皮屏障功能/上皮细胞黏附，并促进巨噬细胞M2极化。机制上，我们发现CircCDKAL1被N6-甲基腺苷（m6A）修饰，这一修饰由甲基转移酶样蛋白3（METTL3）介导。YTH结构域含RNA结合蛋白1（YTHDC1）促进m6A修饰的CircCDKAL1的胞质输出。此外，CircCDKAL1通过与胰岛素样生长因子2 mRNA结合蛋白2（IGF2BP2）相互作用，使 Jumonji 结构域包含蛋白2（JARID2）mRNA不稳定。此外，CircCDKAL1或高迁移率族蛋白B1（HMGB1）沉默可减轻JARID2沉默介导的卵清蛋白诱导的HNEpCs上皮细胞黏附损伤及巨噬细胞M1极化促进作用。总之，METTL3介导的CircCDKAL1的m6A修饰由YTHDC1从细胞核转运至细胞质，通过与IGF2BP2相互作用并调节JARID2/HMGB1轴，促进AR患者巨噬细胞M1极化并损害鼻黏膜上皮屏障功能/上皮细胞黏附。
