ATP/P2X7 signaling as a potential predictive biomarker for early recurrence of nasal polyps: Correlation with inflammasome activation and epithelial barrier dysfunction

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by pronounced epithelial remodeling and barrier dysfunction, contributing to a high rate of postoperative recurrence. However, molecular mechanisms associated with early recurrence remain poorly understood. Methods We performed paired proteomic profiling of nasal polyp tissues obtained from the same patients before initial surgery and at the time of recurrence (discovery cohort) to identify recurrence-associated proteins. Candidate proteins were validated in an independent cohort, and their association with recurrence risk was assessed by receiver operating characteristic (ROC) curve and Kaplan-Meier analyses. The expression and cellular localization of the identified candidate were further characterized by immunofluorescence. Mechanistic investigations were conducted in primary human nasal epithelial cells using ATP stimulation and specific pharmacological inhibitors. Results Paired proteomic analysis identified P2X7, PDE4D, and JADE2 as the top 3 upregulated proteins in recurrent tissues. Among these, only P2X7 was consistently elevated in the validation cohort and predominantly localized to the nasal epithelium (P < 0.01). ROC curve analysis indicated that tissue P2X7 level might serve as a potential predictive marker for postoperative recurrence of CRSwNP. (AUC = 0.678, P=0.022). Kaplan-Meier analysis further showed that the risk of recurrence was significantly higher in the high P2X7 expression group (HR = 2.323, P=0.015). Recurrent tissues exhibited elevated levels of NLRP3 and IL-1β, reduced expression of epithelial barrier markers occludin and E-cadherin, accompanied by increased extracellular ATP concentrations. In vitro, ATP stimulation upregulated P2X7 expression, induced NLRP3 and cleaved IL-1β, and downregulated occludin and E-cadherin. Notably, these effects were reversed by a P2X7-specific inhibitor (A-438079). Conclusion Paired proteomic profiling revealed distinct protein expression profiles between pre- and post-recurrence nasal polyps, with P2X7 serving as a promising predictive biomarker for early recurrence. Mechanistically, the ATP/P2X7 axis may drive disease recurrence by potentially promoting inflammasome activation and epithelial barrier disruption.