CircCramp1l targets the miR-532-3p/HMGB1/Drp1 axis to regulate allergic rhinitis

The pathogenesis of allergic rhinitis (AR) remains incompletely understood, and the role of circular RNAs (circRNAs) in its progression warrants further investigation. This study aimed to elucidate the underlying mechanisms of circRNA-mediated regulation in AR and identify potential therapeutic targets. By collecting nasal mucosa specimens from AR patients, establishing house dust mite(HDM)-induced AR mouse models and human nasal epithelial cell(HNEpCs) models, and combining circRNA/miRNA sequencing with GEO data analysis, it was found that HDM triggers a significant upregulation of circCramp1l in AR. Mechanistically, circCramp1l acts as a ceRNA to sponge miR-532-3p, thereby relieving the suppression of HMGB1, an response-related DAMP molecule. Further validation through dual-luciferase reporter(DLR)assays, Co-IP combined with mass spectrometry, and molecular dynamics(MD) simulations demonstrated that HMGB1 directly binds to Drp1(binding free energy ΔG = -480.02 kcal/mol; key domain: amino acids 86-164 of HMGB1), driving Drp1 Ser616 phosphorylation. This leads to excessive mitochondrial fission, ROS accumulation, P2X7R/TLR4/NLRP3 axis. This signaling cascade induces Th2 polarization(elevated IL-4/IL-5/IL-13), eosinophil infiltration, and epithelial damage. Intervention experiments showed that conditional knockout of HMGB1, silencing of circCramp1l, administration of miR-532-3p mimics, or treatment with the Drp1 inhibitor Mdivi-1 all reversed mitochondrial dysfunction and significantly alleviated AR symptoms. This study reveals that the circCramp1l/miR-532-3p/HMGB1/Drp1 signaling axis contributes to AR pathogenesis by modulating mitochondrial dynamics and P2X7R/TLR4/NLRP3 axis. These results offer a novel target for the diagnosis and treatment of AR.