Epigenetic regulation of inflammatory pathways in chronic rhinosinusitis without nasal polyps: focus on NR3C1 and FCER2

Chronic rhinosinusitis without nasal polyps (CRSsNP) is a common but understudied inflammatory disorder characterized by neutrophilic, Th1- and Th17-skewed immune responses, epithelial barrier dysfunction, and prominent fibrosis. Compared with CRSwNP, patients with CRSsNP frequently exhibit reduced responsiveness to glucocorticoids and higher recurrence rates after surgery. Increasing evidence suggests that epigenetic alterations are associated with features of persistent inflammatory reprogramming.These alterations include DNA methylation, histone modification, and non-coding RNA dysregulation. However, most findings are correlative, and it remains unclear whether these epigenetic changes are causal drivers or secondary consequences of chronic inflammation. This review synthesizes CRSsNP-related epigenetic findings with a focus on two key genes: NR3C1, encoding the glucocorticoid receptor, and FCER2, encoding CD23. Hypermethylation of NR3C1, reduced HDAC2 activity, and microRNA-mediated repression are associated with impaired glucocorticoid signaling and may contribute to the steroid insensitivity observed in CRSsNP. Conversely, hypomethylation of FCER2 and increased CD23 expression correlate with localized IgE production in a subset of patients. Current evidence is limited by small cohort sizes, mixed CRS populations, cross-sectional study designs, and the lack of functional and longitudinal studies needed to establish causality. Environmental factors—including tobacco smoke, particulate air pollution, and Staphylococcus aureus biofilms—have been associated with epigenetic alterations that may contribute to chronic inflammation.