BACKGROUND: Regulation of epithelial cell death has emerged as a key mechanism maintaining immune homeostasis in the airway. However, the mechanisms governing epithelial cell survival in nasal polyps (NPs) remains poorly understood. OBJECTIVE: To investigate the ferroptosis of nasal epithelial cell and its implications in the pathogenesis of NPs. METHODS: The cell death, lipid peroxidation, and ferrous iron levels in nasal epithelial cells were determined by flow cytometry. Biomarkers and signaling pathways associated with ferroptosis were evaluated by quantitative RT-PCR, single-cell and bulk RNA-sequencing, immunofluorescence staining, and western blotting. Human nasal epithelial cells (HNECs) and 16HBE cells were stimulated with different agents. Mitochondrial ultrastructure in HNECs were visualized by transmission electron microscopy. Cytokine levels were quantified using ELISA. A cigarette smoke extract (CSE)-induced mouse model was established and treated with deferoxamine. RESULTS: Nasal epithelial cells from both eosinophilic and noneosinophilic NPs showed intensified lipid peroxidation and altered mitochondrial morphology, resembling the features of ferroptosis. Ferroptosis triggered C-X-C motif ligand (CXCL)8 production in 16HBE cells and HNECs through the activation of mitogen-activated protein kinase pathway. CSE exposure elevated ferrous iron levels by upregulating transferrin receptor 1, led to ferroptosis and subsequent CXCL8 production in HNECs. Deferoxamine treatment inhibited nasal epithelial cell ferroptosis, CXCL8 levels, and neutrophilic numbers in a CSE-induced mice model. Smoking burden was correlated with CXCL8 levels and neutrophil infiltration in patients with NPs. An analysis of 494,176 UK Biobank participants revealed smoking as a risk factor for NPs (Odds Ratio: 1.346, 95% Confidence Interval: 1.245-1.456, P <
0.001). CONCLUSION: Smoking-induced ferroptosis promotes CXCL8 production in nasal epithelial cells and thus potentially exacerbates neutrophilic inflammation in NPs.