DLX5 regulates nasal Epithelial Mesenchymal Transition and inflammation in EosCRSwNPs via the COL1A1-mediated Wnt/β-catenin Signaling.

Eosinophilic chronic rhinosinusitis with nasal polyps (EosCRSwNP) is a multifaceted and refractory inflammatory condition, characterized by a troubling propensity for recurrence and complex underlying pathophysiology. A critical aspect driving its progression is the epithelial-mesenchymal transition (EMT) combined with sustained chronic inflammation within the nasal mucosa. However, the upstream regulatory mechanisms orchestrated by epithelial cells remain insufficiently elucidated. In this study, we employed an RNA-sequencing-based transcriptomics approach to profile nasal mucosal tissues across distinct CRSwNP subtypes, uncovering differentially expressed proteins and conducting integrative correlation analyses. Our investigation revealed a significant upregulation of the homeobox gene DLX5 in the nasal epithelium of patients with EosCRSwNP, suggesting its pivotal role in both EMT and the persistence of chronic inflammation in the nasal epithelium. Functional assays utilizing primary human nasal epithelial cells demonstrated that DLX5 overexpression directly drives EMT progression and exacerbates inflammatory responses, leading to mucosal remodeling marked by increased expression of mesenchymal markers and pro-inflammatory cytokines. Mechanistically, we identified that DLX5 dysregulates Wnt/β-catenin signaling homeostasis via the profibrotic mediator collagen type I alpha 1 chain (COL1A1). This interaction simultaneously enhances both EMT and inflammatory activation. Our findings elucidate a novel regulatory axis in which DLX5 overexpression exacerbates disease pathogenesis through COL1A1-dependent modulation of Wnt/β-catenin signaling, thereby promoting both structural and inflammatory perturbations characteristic of EosCRSwNP. This study not only advances our understanding of the mechanistic pathways underlying persistent inflammation and the elevated recurrence rate in EosCRSwNP but also highlights potential therapeutic targets for innovative gene-directed interventions.