SLC27A2 marks lipid peroxidation in nasal epithelial cells driven by type 2 inflammation in chronic rhinosinusitis with nasal polyps

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by persistent inflammation and epithelial cell dysfunction, but the underlying molecular mechanisms remain poorly understood. Here we show that dysregulated lipid metabolism and increased lipid peroxidation in nasal polyp epithelial cells contribute to the pathogenesis of CRSwNP. Integrated analysis of bulk and single-cell RNA sequencing data reveals upregulation of SLC27A2/FATP2 in nasal polyp epithelium, which correlates with increased lipid peroxidation. SLC27A2-positive epithelial cells exhibit enriched expression of lipid peroxidation pathway genes and enhanced responsiveness to IL-4/IL-13 signaling from Th2 and ILC2 cells. Inhibition of IL-4/IL-13 signaling by dupilumab reduces expression of lipid peroxidation-associated genes, including SLC27A2. In eosinophilic CRSwNP, SLC27A2 expression correlates with disease severity. Pharmacological inhibition of FATP2 in air-liquid interface cultures of nasal epithelial cells decreases expression of IL13RA1 and lipid peroxidation-related genes. Our findings identify FATP2-mediated lipid peroxidation as a key driver of epithelial dysfunction and inflammation in CRSwNP, providing new insights into disease mechanisms and potential therapeutic targets.