Glycolysis-high SPP1⁺ macrophages promote inflammation and tissue remodeling through the SPP1-CD44 axis in eosinophilic chronic rhinosinusitis with nasal polyps

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by persistent mucosal inflammation and marked clinical heterogeneity, yet the contribution of metabolic dysregulation to disease pathogenesis remains poorly defined. This study aimed to elucidate the role of glycolytic reprogramming in CRSwNP, with a particular focus on eosinophilic CRSwNP (eCRSwNP). Integrated analyses of publicly available bulk RNA-seq data from GSE136825 (28 controls and 42 CRSwNP samples) and single-cell RNA sequencing data from HRA000772 (5 controls, 5 neCRSwNP, and 6 eCRSwNP samples) were performed to characterize metabolic alterations across distinct cell populations in CRSwNP. Glycolytic activity was quantified using pathway enrichment and module scoring approaches. Seurat was used for single-cell analysis, Monocle3 for macrophage trajectory analysis, and CellChat for cell–cell communication analysis. Key findings were further validated in independently collected human nasal tissue samples using RT-qPCR, immunohistochemistry (IHC), and immunofluorescence (IF). A murine model of eCRSwNP was established, and glycolysis was pharmacologically inhibited using 2-deoxy-D-glucose (2-DG) to assess its effects on inflammation and tissue remodeling. Glycolytic activity was markedly elevated in nasal polyp tissues, especially in eCRSwNP, with myeloid cells exhibiting the most pronounced metabolic reprogramming. A distinct subset of glycolysis-high, M2-like macrophages characterized by high expression of SPP1 (SPP1⁺ macrophages) was selectively enriched in eCRSwNP and positively correlated with disease severity. These macrophages were actively involved in Th2 inflammatory responses and extracellular matrix remodeling. SPP1⁺ macrophages communicated with Th2 cells, ILC2s, and fibroblasts predominantly through SPP1-CD44 signaling. Importantly, glycolysis inhibition with 2-DG significantly attenuated sinonasal inflammation, polyp-like lesion formation, and collagen deposition in vivo, accompanied by a reduced accumulation of pathogenic SPP1⁺ macrophage subsets. This study identifies glycolysis-high SPP1⁺ macrophages as a key pathogenic subset in eCRSwNP and implicates SPP1-CD44-mediated crosstalk as a potential mechanism underlying disease progression. Targeting macrophage glycolysis may represent a potential therapeutic strategy for this disease. 1. Glycolysis is markedly enhanced in CRSwNP, particularly in eCRSwNP. 2. SPP1⁺ macrophages are expanded in eCRSwNP and exhibit M2-like features with elevated glycolytic activity. 3. SPP1⁺ macrophages communicate with Th2 cells, ILC2s, and fibroblasts predominantly through SPP1-CD44 signaling. 4. Glycolysis inhibition by 2-DG alleviates nasal inflammation and suppresses metabolic reprogramming in the nasal mucosa.