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In this paper, we show that mitochondrial metabolism-related genes (MM-RGs) play a critical role in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). This is significant because, by integrating transcriptomic and single-cell RNA sequencing data, we identified five key biomarkers—CYP2J2, CYBB, ALOX5, PLB1, and PLA2G2A—which are enriched in immune-related pathways and strongly associated with M2 macrophage and plasma cell infiltration. Furthermore, our predictive nomogram and identification of epithelial and T cells as primary mediators, alongside validation through RT-qPCR, highlight novel diagnostic and therapeutic avenues for CRSwNP.