Integrated Transcriptomic and Structural Biophysical Analysis of Cysteinyl Leukotriene Receptors in Chronic Rhinosinusitis with Nasal Polyps

Background: Leukotriene receptor antagonists used in airway disease predominantly inhibit CysLT1R, whereas the relative disease-associated expression and structural context of CysLT1R and CysLT2R in chronic rhinosinusitis with nasal polyps (CRSwNP) remain incompletely resolved. Methods: We reanalyzed deposited transcriptomic data from GSE136825 using DESeq2 and two independent microarray cohorts (GSE36830 and GSE23552) using limma. A patient-blocked sensitivity analysis was performed in 30 complete nasal-polyp/nonpolyp-inferior-turbinate pairs reconstructed from public GSE136825 sample titles. Immune deconvolution was re-audited with Benjamini–Hochberg correction across all 22 LM22 cell types. For the five leukotriene-pathway genes specifically requested during peer review (ALOX5, ALOX5AP, LTC4S, CYSLTR1, and CYSLTR2), we performed a targeted evidence extraction from publicly accessible disease-specific nasal-polyp single-cell RNA-sequencing studies. We also performed a coordinate-based secondary analysis of antagonist-bound CysLT1R and CysLT2R structures. Results: In GSE136825, both CYSLTR1 (log2FC 1.317, 95% CI 0.913–1.720; adjusted p = 1.19 × 10−8) and CYSLTR2 (log2FC 3.390, 2.393–4.386; adjusted p = 2.38 × 10−9) were increased in polyp tissue. Positive effect estimates were also observed in both validation cohorts; CYSLTR2 did not pass genome-wide FDR correction in the small GSE36830 cohort (adjusted p = 0.159). In the 30 reconstructed pairs, patient-blocked DESeq2 again estimated increased CYSLTR1 (log2FC 0.769, 0.427–1.112; adjusted p = 3.93 × 10−4) and CYSLTR2 (1.835, 1.031–2.639; adjusted p = 3.02 × 10−4). Corrected immune-deconvolution q-values were 0.0088 for eosinophils, 0.0099 for M2 macrophages, and 0.0154 for activated mast cells. Disease-specific nasal-polyp single-cell evidence places ALOX5/ALOX5AP/LTC4S and CYSLTR1 predominantly in mast cells, whereas CYSLTR2 is prominent in myeloid cells and is also detected in nasal-polyp eosinophils. Coordinate analysis showed an aligned pocket Cα RMSD of 1.84 Å between antagonist-bound CysLT1R (6RZ4) and CysLT2R (6RZ6), while the antagonist-bound CysLT2R ensemble retained a highly conserved pocket backbone (0.08–0.30 Å) with ligand-dependent contact-network variation. Conclusions: The corrected analyses support increased expression of both cysteinyl leukotriene receptors in CRSwNP, with descriptively larger CYSLTR2 effect estimates in the analyzed contrasts. These data do not establish a receptor imbalance, a pro-inflammatory role for CysLT2R, or a mechanistic explanation for treatment response. Disease-specific protein localization and receptor-selective functional studies remain necessary.