Distinct Functional Signatures of Human Olfactory and Respiratory Mucus Revealed by Proteomics Combined With Machine Learning

BACKGROUND: The nasal cavity includestwo distinct epithelial regions: olfactory and respiratory which fulfilldifferent roles. Despite their differences, their mucus composition, however, is yet not well elucidated. METHODS: To analyze themucosal secretome, samples from the human olfactory mucus (OM) and respiratorymucus (RM) were collected in a volunteer study with 25 normosmic individualsand analyzed using label-free quantitative proteomics (LFQ), supervised machinelearning (Partial Least Squares Discriminant Analysis, PLS-DA), functionalenrichment via Gene Ontology (GO) and pathway analyses at Reactome database. RESULTS: A total of 1,780high-confidence proteins were quantified across 50 samples. The optimizedPLS-DA model achieved robust discrimination between OM and RM (AUC = 0.93 ±0.04), identifying distinct molecular signatures. Cross-validation across GO,Reactome, and PLS-DA macro-category analyses confirmed the robustness andbiological coherence of these findings. CONCLUSIONS: Overall, this study defines twocomplementary mucosal ecosystems: a dynamic olfactory mucus optimized for highmitochondrial activity, (non-motile) ciliary renewal, and autophagy, and animmune-active respiratory mucus specialized in host defense, providing acomprehensive molecular framework of nasal regional specialization.