From respiratory infections to environmental exposures: CC16 is a key modulator of airway homeostasis.

Club cell secretory protein 16 (CC16; SCGB1A1) is a multifunctional secretoglobin predominantly produced by nonciliated airway epithelial cells and is increasingly recognized as a central regulator of airway homeostasis. Beyond its long-standing role as a biomarker of epithelial integrity, accumulating clinical and experimental evidence highlights CC16 as an active modulator of inflammation, host defense, redox balance, and tissue remodeling. Reduced CC16 levels are a consistent feature of chronic inflammatory lung diseases, including asthma, chronic obstructive pulmonary disease, and cystic fibrosis, as well as following diverse environmental and occupational exposures. Alterations in CC16 dynamics are also observed during respiratory infections, where compartment-specific changes in CC16 concentrations reflect epithelial injury, barrier dysfunction, and disease severity. Mechanistically, CC16 exerts anti-inflammatory and antimicrobial effects through interactions with integrins, lipid mediators, and innate immune signaling pathways in both epithelial and immune cells, while also contributing to antioxidant defense and mitochondrial homeostasis. Environmental exposures, including tobacco smoke, air pollutants, and xenobiotics, profoundly influence CC16 expression in a context- and duration-dependent manner, whereas factors such as retinoids can restore CC16 production and epithelial repair. In this review, we synthesize current clinical, experimental, and mechanistic evidence to define the multifaceted roles of CC16 in airway biology, emphasize its relevance to susceptibility and outcomes in respiratory disease, and highlight critical knowledge gaps that must be addressed to advance CC16 as both a biomarker and therapeutic target.