Mucus and inflammation in the HEMT Era: Persistent barriers to complete airway normalization in cystic fibrosis

Cystic fibrosis (CF) is an epithelial ion transport disorder that dehydrates the airway surface, concentrates mucus, and disrupts mucociliary clearance (MCC). Beyond reduced chloride/bicarbonate secretion and elevated ENaC activity, shifts in the composition, structure, and packaging of the gel-forming mucins MUC5AC and MUC5B reshape mucus viscoelasticity and adhesion, promoting stasis, infection, and inflammation. We synthesize mechanistic advances showing how CFTR dysfunction and microenvironmental cues, particularly epithelial hypoxia with HIF-driven ENaC activation and IL-1 cytokine signaling, reinforce hyperconcentration, alter MUC5AC/MUC5B balance, impede submucosal gland discharge, and foster a self-perpetuating cycle of protease-rich inflammation. Highly effective CFTR modulator therapies, such as elexacaftor/tezacaftor/ivacaftor, improve hydration, MCC, and inflammation; however, residual rheologic abnormalities, inflammation, persistent or recurrent infection, and regional heterogeneity are common, indicating that CFTR restoration alone does not uniformly normalize the airway milieu. We highlight methodological advances that enable quantitative, surface-level readouts in patient-derived air-liquid-interface cultures (e.g., FRAP and magnetic micro-wire rheology) linking thin-layer mucus viscosity, network mechanics, and transport to cellular physiology. Integrating these assays with clinical measures (e.g., MCC, segmental pathogen and protease burden) supports a comprehensive model in which CFTR loss initiates mucus hyperconcentration that is subsequently enhanced by mucin entanglement/interactions and hypoxia-inflammatory feedback. Finally, we propose an integrated therapeutic framework that pairs CFTR correction with mechanism-guided, mucus-targeted interventions and data-driven anti-infective/anti-inflammatory strategies to optimize personalized treatment approaches.