Activation of pyroptosis impairs basal cell differentiation in the nasal epithelium in chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory sinus disease, which is categorized into eosinophilic CRSwNP (ECRSwNP) and non‑ECRSwNP (nECRSwNP), affecting 2‑4% of the population. Pyroptosis is implicated in the pathogenesis of CRSwNP, although the underlying molecular mechanisms driving pyroptosis and its role in the onset and progression of CRSwNP remain incompletely understood. Nasal tissue specimens from ECRSwNP and nECRSwNP were collected and analyzed by hematoxylin and eosin, immunohistochemical (IHC) staining of pyroptosis‑related markers, including NLRP3 and IL‑1β. Immunofluorescence (IF) staining was used to evaluate cleaved gasdermin D (GSDMD) and Caspase‑1 expression. Primary human nasal epithelial cells (HNEpCs) were isolated and cultured to investigate inflammatory mechanisms in vitro. Western blotting and reverse transcription‑quantitative PCR (RT‑qPCR) were performed to quantify expression of inflammasome‑related genes and proteins. RNA‑sequencing (RNA‑seq) was performed to identify differentially expressed genes and enriched pathways using DESeq2 and DAVID for functional annotation. The present study demonstrated the presence of pyroptosis features, characterized by elevated expression of NLRP3 and IL‑1β, in human samples from patients with ECRSwNP and nECRSwNP patients, with increased signals observed in nECRSwNP compared with ECRSwNP samples. Furthermore, IL‑5 and IL‑17A were identified in peripheral venous serum as key triggers of pyroptosis in ECRSwNP and nECRSwNP, respectively. Additionally, activation of pyroptosis disrupts the differentiation of basal cells, favoring goblet cell differentiation, the primary hallmark of CRSwNP. Inhibition of pyroptosis restores the balance of differentiation in basal cells by suppressing inflammation and metabolism pathways. The present findings highlight pyroptosis as a key pathological driver in CRSwNP and suggest that targeting pyroptosis may offer a novel therapeutic strategy to restore epithelial homeostasis and alleviate disease symptoms.