SLC27A2 as a molecular marker of impaired epithelium in chronic rhinosinusitis with nasal polyps

Abstract

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex disease characterized by multiple inflammatory endotypes. Although recent progress has been made in endotype-based classification, developing tailored therapeutic strategies for CRSwNP remains challenging. This study aimed to optimize therapeutic outcomes in CRSwNP by identifying potential molecular markers. Methods: We utilized an integrated approach that combined bulk and single-cell RNA sequencing (scRNA-seq) to delineate the molecular signatures inherent to the cellular components of nasal polyp (NP) tissue. The levels of C11-BODIPY (as a marker of lipid peroxidation) and SLC27A2/FATP2 were assessed using quantitative PCR and immunofluorescence (IF) staining. The effects of lipofermata, a FATP2 inhibitor, were examined in air-liquid interface (ALI) cultured epithelial cells derived from CRSwNP patients and healthy controls. Results: Deconvolution analysis of NP tissue revealed an upregulation of genes associated with lipid metabolism in the NP epithelium. In CRSwNP patients, we observed a significant increase in lipid peroxidation and SLC27A2/FATP2 expression in the NP epithelium. A marked expression of genes critical to metabolic pathways involved in lipid peroxidation was identified in SLC27A2-positive epithelial cells. Additionally, FATP2 and lipid peroxidation staining patterns exhibited a positive correlation in their respective % Area levels. Elevated SLC27A2 expression was associated with disease pathogenesis and correlated with disease severity. Treatment with lipofermata resulted in decreased mRNA levels of ALOX15, a key mediator of inflammation and lipid peroxidation, and FOXJ1, a marker of abnormal ciliogenesis. Conclusion: Elevated SLC27A2 expression in the NP epithelium correlates with the severity of CRSwNP, highlighting its potential as a therapeutic target for managing advanced CRSwNP cases.