MUC16 Defines a Fibrotic Endotype With Corticosteroid Insensitivity in Nasal Polyps

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.

To determine whether MUC16 is associated with fibrosis and corticosteroid insensitivity in CRSwNP and to define its functional effects in fibroblasts and epithelial cells.

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.

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.

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.