MUC16 Defines a Fibrotic Endotype With Corticosteroid Insensitivity in Nasal Polyps

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disease in which persistent remodeling and fibrosis may contribute to corticosteroid refractoriness. Membrane-tethered mucins, particularly MUC16, may regulate profibrotic and steroid-response pathways. OBJECTIVES: To determine whether MUC16 is associated with fibrosis and corticosteroid insensitivity in CRSwNP and to define its functional effects in fibroblasts and epithelial cells. METHODS: Nasal polyp tissue from CRSwNP subgroups, including oral corticosteroid-resistant patients, was analyzed by histology, immunohistochemistry, hydroxyproline quantification, and RT-qPCR. Primary nasal polyp fibroblasts and epithelial cells, and MRC5, BEAS2B, and HeLa cells, were stimulated with TGF-β1 or LPS and treated with dexamethasone. MUC16 was silenced with siRNA, and profibrotic and glucocorticoid-response pathways were evaluated. RESULTS: Oral corticosteroid-resistant polyps showed the highest fibrosis (collagen, α-SMA-positive fibroblasts, TGF-β1, hydroxyproline), despite not being the most eosinophilic. MUC16 increased in these polyps and correlated with hydroxyproline. Their fibroblasts, overexpressing MUC16, showed reduced dexamethasone inhibition of TGF-β1-induced collagen I and proliferation. MUC16 silencing reduced phospho-SMAD3 and Smad-binding element activity, restored dexamethasone sensitivity, and reduced proliferation. In epithelium, MUC16 silencing enhanced dexamethasone suppression of LPS-induced IL-6, reduced STAT3 phosphorylation, and increased glucocorticoid response element activity, GR Ser211 phosphorylation, and MKP1 induction. CONCLUSIONS: In human polyp tissue, MUC16 is associated with a fibrotic, corticosteroid-insensitive CRSwNP phenotype, whereas its causal link with impaired glucocorticoid signaling is supported by in vitro loss-of-function experiments. MUC16 may represent a candidate biomarker and potential therapeutic target in refractory CRSwNP, although prospective validation as an endotype-defining biomarker is still required.