Lonidamine alleviates inflammation and tissue remodeling in a mouse model of eosinophilic chronic sinusitis: A single-cell transcriptomics study

BACKGROUND: Eosinophilic chronic sinusitis (ECRS) is a refractory condition resistant to therapies and prone to relapse. Hexokinase 2 (HK2), a key glycolysis enzyme, regulates inflammation but its role in ECRS is unclear. METHODS: An ECRS mouse model was established using intranasal administration of papain. Single-cell RNA sequencing (scRNA-seq) was employed to analyze the expression patterns of Hk2 in ECRS. The HK2 inhibitor lonidamine (LND) was administered orally to assess symptoms, inflammatory cells and cytokines in the nasal lavage fluid (NALF), serum total IgE, and pathological characteristics of nasal mucosal inflammation. Mechanistic insights were investigated using scRNA-seq and an in vitro human nasal epithelial cells (HNEpC) model stimulated with IL-4, IL-13, and TNF-α. RESULTS: Elevated Hk2 expression was found in the nasal mucosa in the ECRS model. LND alleviated ECRS symptoms, reducing sneezing, cytokine release, inflammatory cell infiltration, and goblet cell hyperplasia. Epithelial cell damage was identified as a key driver of inflammation and remodeling. LND suppressed inflammation by inhibiting differentiation of inflammatory epithelial cells and neutrophils via Cxcl1-Cxcr2. Additionally, LND reduced epithelial cell-induced nasal mucosal remodeling by inhibiting the Ptn-Ncl signaling pathway between epithelial cells and neurons. In the in vitro experiment, LND significantly and dose-dependently reduced both CXCL1 and PTN expression, confirming its direct anti-inflammatory and anti-remodeling effects on nasal epithelial cells. CONCLUSIONS: LND significantly suppressed nasal inflammation and tissue remodeling in the ECRS model. These findings suggest that HK2 inhibition holds promise as a safe and effective therapeutic approach for the management of ECRS.