BackgroundSquamous metaplasia is commonly observed in eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP). However, its underlying mechanisms remain unclear. This study aimed to evaluate the role of glucose transporter 1 (GLUT1) in the development of squamous metaplasia in eCRSwNP.MethodsTissue proteomics was employed to identify disease-specific proteins in eCRSwNP. Immunofluorescence, western blotting, and RT-qPCR were used for validation. Human nasal epithelial cells were utilized to assess GLUT1 expression and its regulatory mechanisms. A chronic rhinosinusitis with nasal polyps (CRSwNP) mouse model was used to examine the effect of GLUT1 inhibition on squamous metaplasia and nasal inflammation.ResultsProteomic analysis revealed a disease-specific protein expression profile in eCRSwNP polyps. Cohort validation demonstrated that GLUT1 and keratin 13 (KRT13) expression levels were significantly higher in the eCRSwNP group, with expression primarily localized in the epithelial regions. GLUT1 expression was positively correlated with the incidence of squamous metaplasia as well as KRT13 and involucrin (IVL) expression. In vitro experiments confirmed that combined Interleukin (IL)-4/IL-13 treatment upregulated GLUT1, KRT13, and IVL expression in human nasal epithelial cells in a dose-dependent manner, whereas GLUT1 inhibition reduced KRT13 and IVL expression, possibly through suppression of the PI3K-AKT signaling pathway. Animal experiments demonstrated that GLUT1 inhibition alleviated squamous metaplasia and inflammation in the nasal mucosa of mice.ConclusionElevated GLUT1 expression plays a key role in driving squamous metaplasia in eCRSwNP. GLUT1 inhibition attenuates nasal epithelial squamous metaplasia and inflammation in CRSwNP.