Systematic elucidation of the cross-omics regulatory network in chronic rhinosinusitis: the LAT-IL23R metabolic axis

OBJECTIVE: The pathological mechanisms underlying Chronic Rhinosinusitis (CRS) remain incompletely understood, and current treatments exhibit low response rates alongside a scarcity of specific drugs targeting the disease's fundamental characteristics. Although dysregulation of protein interactions and metabolic reprogramming have been confirmed as contributors to the progression of CRS, a systematic elucidation of the cross-omics regulatory network encompassing genetics, proteins, and metabolites is still needed. METHODS: This study employed a multi-stage comprehensive analytical strategy that integrates MR, mediation analysis, and proteomics. Initially, using pQTL data from the deCODE and UKB-PP databases, as well as CRS GWAS data from the FinnGen database, MR was utilized to identify proteins associated with CRS. Following this, a two-step mediation analysis was conducted to construct a protein-protein-metabolic regulatory network. RESULTS: The study identified that the LAT-IL23R metabolic axis mediates CRS through γ-glutamyltyrosine and trans-4-hydroxyproline. CONCLUSION: This study systematically reveals, for the first time, the promoting role of the LAT-IL23R-amino acid metabolic network in CRS, providing a theoretical basis for the development of targeted combination therapies. LEVEL OF EVIDENCE: Level 3 (causal inference from cohort-derived genetic data).