Dysregulated glycosaminoglycan biosynthesis and retinoid metabolism in chronic rhinosinusitis with nasal polyps: insights from a comprehensive transcriptomic analysis

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Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common inflammatory condition affecting 5-12% of the population. Despite its prevalence, the underlying pathophysiological mechanisms remain incompletely understood, representing an unmet medical need. Next-generation sequencing coupled with bioinformatic analysis allows to characterize the global transcriptomic profile, identify key mechanisms, pathways, and potential novel drug targets. Methods: mRNA sequencing was performed on 16 nasal polyps (CRSwNP-NP) and paired nasal mucosa (CRSwNP-NM) samples from patients with recurrent CRSwNP and on 15 nasal mucosa samples from non-CRS controls (CS-NM). Differentially expressed genes (DEGs) were determined, and enrichment analyses were performed using the Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Reactome databases and Ingenuity Pathway Analysis. Results: CRSwNP-NP tissues were differentiated from CS-NM by 183 DEGs and from CRSwNP-NM by 293 DEGs. When comparing nasal mucosa from CRS and non-CRS patients, 192 DEGs were identified. Enrichment analysis of nasal polyp tissues revealed that the most significantly upregulated gene sets were involved in positive regulation of extracellular signal-regulated kinase 1/2 cascade, hypoxia-inducible factor-1 pathway, overactivation of renin-angiotensin-aldosterone system and ferroptosis. Conversely, the downregulated gene sets were predominantly associated with impaired antimicrobial functions. Comparing patients and healthy controls' nasal mucosal sample, glycan metabolism was significantly upregulated, while retinol metabolism was downregulated. Conclusion: The main pathways in the polyps are associated with tissue remodeling, increased renin-angiotensin-aldosterone system activation, ferroptosis, decreased antimicrobial defense as local microenvironmental risk factors contributing to the recurrence of CRSwNP. Upregulated glycosaminoglycan biosynthesis and downregulated retinol metabolism could represent a systemic susceptibility factor.

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