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 can be categorized into eosinophilic CRSwNP (ECRSwNP) and non-eosinophilic CRSwNP (nECRSwNP), affecting approximately 2-4 percent of the population. Recent studies have implicated pyroptosis 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. Here, we demonstrate the presence of pyroptosis features in both ECRSwNP and nECRSwNP samples, with higher signals observed in nECRSwNP compared to ECRSwNP samples. Furthermore, we identify IL-5 and IL-17A in peripheral venous serum as major triggers of pyroptosis in ECRSwNP and nECRSwNP, respectively. Additionally, activation of pyroptosis disrupts the differentiation of basal cells, favoring goblet cell differentiation, the main hallmark of CRSwNP. Intriguingly, inhibition of pyroptosis restores the balance of differentiation in basal cells by suppressing inflammation and metabolism pathways.Our 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.