BDNF as a Key Mediator in Eosinophilic Inflammation in CRSwNP: Insights From Transcriptomic and Functional Analysis

ABSTRACT Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disorder characterized by eosinophil‐driven pathology. While neurotrophins, particularly brain‐derived neurotrophic factor (BDNF), have been implicated in eosinophilic inflammation in allergic conditions, their involvement in CRSwNP remains undefined. Methods Bulk‐RNA sequencing of 23 nasal mucosa samples and ELISA quantification of 95 nasal secretions were conducted to evaluate BDNF expression across CRSwNP endotypes and its correlation with eosinophil infiltration and clinical severity. Cellular BDNF sources were mapped using immunofluorescence staining and single‐cell RNA sequencing. Primary human nasal epithelial cells (HNECs) were stimulated to investigate cytokine‐mediated BDNF regulation, while recombinant BDNF was applied to assess its functional effects on eosinophil survival, activation, and migration via flow cytometry and transwell assays. Results Transcriptomic profiling linked BDNF to Th2‐skewed and eosinophilic inflammation signatures. Tissue and secretory BDNF levels were elevated in eosinophilic CRSwNP (ECRSwNP) versus controls, showing strong correlations with eosinophil infiltration and disease severity. BDNF level in nasal secretion demonstrated moderate diagnostic accuracy for ECRSwNP. IL‐4/IL‐13 stimulation upregulated BDNF via JAK/STAT signaling in HNECs. Exogenous BDNF enhanced eosinophil survival and migration through its high‐affinity receptor, tropomyosin receptor kinase B (TrkB). Conclusion This study positions BDNF as a key orchestrator of epithelial‒eosinophil crosstalk in CRSwNP, perpetuating inflammation through Th2‐primed BDNF secretion and eosinophil persistence. Therapeutic modulation of this axis may offer novel precision strategies for eosinophilic CRSwNP management.