MUC1 in the upper-lower airway inflammatory continuum: an endotype-centered perspective

Emerging evidence indicates that upper and lower airway diseases share anatomical and pathophysiological features. Infections often begin in the upper airway and progress downward, suggesting common immunological mechanisms. Mucin 1 (MUC1), a membrane-bound glycoprotein abundantly expressed in airway epithelial cells, has attracted increasing attention for its immunoregulatory and barrier functions. This review summarizes recent findings on MUC1's involvement in airway inflammation driven by Th1, Th2, and Th17 immune responses. In Th1-type inflammation, MUC1 negatively regulates Toll-like receptor (TLR)-NF-κB signaling pathways, thereby limiting excessive inflammatory responses to bacterial and viral infections. In Th2-type inflammation, MUC1 influences eosinophil survival, maintains epithelial integrity, and modulates glucocorticoid sensitivity, exerting both protective and pathological effects. In Th17-type inflammation, characterized by neutrophil infiltration and elevated IL-17A and IL-22, MUC1 expression alleviates chronic inflammation and may impact microbiome dysbiosis. While MUC1's roles in lower airway disorders are increasingly understood, its specific function and regulatory mechanisms in upper airway diseases remain unclear. This review adopts the unified airway disease (UAD) framework to examine the endotype-specific roles of MUC1 across the upper and lower airways. Rather than providing a disease-by-disease summary, we synthesize evidence through Th1/Th2/Th17 endotypes, link shared mechanisms to biomarker-based patient stratification, and outline MUC1-targeted therapeutic strategies. By applying an endotype- and UAD-centered perspective, the review distinguishes itself from previous work and highlights actionable opportunities for precision medicine. Furthermore, we emphasize the translational potential of MUC1 as both a diagnostic biomarker and a therapeutic target, focusing on advances in small peptides, monoclonal antibodies, RNA interference, and natural compounds that modulate MUC1-related pathways. These developments may ultimately enable the creation of personalized therapies for airway inflammation.