Widely Targeted Lipidomics of Nasal Fluid Across Upper-Airway Inflammation: Phenotype-Associated Remodeling in Allergic Rhinitis and Chronic Rhinosinusitis with Nasal Polyps

Allergic rhinitis (AR) and chronic rhinosinusitis with nasal polyps (CRSwNP) share overlapping inflammatory mechanisms while retaining distinct disease biology. Although lipid metabolism is increasingly implicated in airway inflammation, the nasal fluid lipidomic landscape across AR and CRSwNP and its relationship to local eosinophilic inflammation and clinical burden remain incompletely understood. We performed widely targeted liquid chromatography–tandem mass spectrometry (LC-MS/MS) lipidomics on nasal fluid from 73 participants, including 22 controls, 23 patients with AR, and 28 patients with CRSwNP. Group differences were evaluated using multivariate analysis and models adjusted for age, sex, and smoking status, followed by trajectory clustering and residual-correlation network analysis. Within CRSwNP, adjusted models were used to assess lipid associations with tissue eosinophilia, the 22-item Sinonasal Outcome Test (SNOT-22), overall visual analog scale (VAS), and Lund–Mackay computed tomography score. Lipid subclass patterns were examined by ranked enrichment and focused subclass score analyses. AR was characterized mainly by higher relative abundances of TG species, whereas CRSwNP showed broader increases involving triacylglycerol species, plasmalogen phosphatidylethanolamines, and lysophospholipids. Exploratory clustering of 147 lipids showing nominally significant differences (p < 0.05) in at least one covariate-adjusted pairwise group comparison yielded four modules with differing biochemical compositions, although the partition was sensitive to the input lipid set. Among these, the diacylglycerol–lysophosphatidic acid-related module displayed strong internal network connectivity, suggesting coordinated variation within the identified module. Within CRSwNP, ranked analysis of lipid associations with tissue eosinophilia showed negative enrichment of plasmalogen phosphatidylethanolamine, sphingomyelin, and ether-linked lysophosphatidylcholine, and positive enrichment of glycerolipid and acylcarnitine subclasses. Clinical burden showed only partial overlap with this pattern: plasmalogen phosphatidylethanolamine was inversely associated with both tissue eosinophilia and patient-reported symptom burden, whereas conventional lysophosphatidylcholine showed stronger positive associations with symptomatic and radiographic burden. These findings suggest distinct and coordinated nasal fluid lipidomic features associated with the upper-airway inflammatory phenotype, local eosinophilic inflammation, and clinical disease burden.