CTSS as a novel biomarker for tissue remodeling in CRSwNP: insights from multi-omics research.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a refractory, relapsing upper airway inflammatory disorder cha-racterized by prominent tissue remodeling. Current therapeutic options remain suboptimal. We aimed to identify novel potential targets and biomarkers using integrative multi-omics. METHODOLOGY: We performed Mendelian randomization (MR) analyses integrating blood expression quantitative trait loci (eQTL) from eQTLGen and plasma protein quantitative trait loci (pQTL) from deCODE with nasal polyps (NP) genome-wide association study data from 8,496 NP patients and 371,520 controls. Significant targets underwent validation via bulk/single-cell RNA sequen-cing, immunohistochemistry, and immunofluorescence. RESULTS: MR analyses identified 6 targets causally linked to NP risk in both eQTL and pQTL analyses. Therein, cathepsin S (CTSS) increased the risk of NP, exclusively demonstrating colocalization with NP and exhibiting significant upregulation in NP tissue. Single-cell data showed CTSS mainly express in monocyte/macrophages, and CTSS-high subsets enriched in CRSwNP vs. Control. Immunohistochemistry and immunofluorescence further confirmed high CTSS expression in NP. Moreover, CTSS expression cor-related with tissue remodeling pathways and associated with CRSwNP clinical severity. CONCLUSIONS: CTSS may contribute to the pathogenesis of CRSwNP by modulating tissue remodeling. CTSS is a noval biomarker for CRSwNP.