The FOXA2/ST3GAL4 axis regulates airway mucus hypersecretion by modulating the ERK/NF-κB pathway

Airway mucus hypersecretion is a pathophysiological process characterized by excessive mucus production driven by diverse pathogenic factors, which exacerbates clinical outcomes in susceptible populations by increasing morbidity and mortality. MUC5AC, the predominant mucin secreted by airway goblet cells, serves as one of the definitive biomarker for quantifying the severity of mucus hypersecretion. Forkhead box A2 (FOXA2) is highly expressed in airway and alveolar type II epithelial cells, its downregulation is associated with mucus hypersecretion and impaired mucociliary clearance. Although ST3 beta-galactoside alpha-2,3-sialyltransferase 4 (ST3GAL4), a key glycosyltransferase gene, plays a critical role in cell-cell interactions and immune responses, its specific function within the airway remains unexplored. This study examines the interaction between FOXA2 and ST3GAL4 in regulating airway mucus hypersecretion. An in vivo murine model of mucus hypersecretion was developed using C57BL/6 mice, which underwent intratracheal instillation with P. aeruginosa PAO1 to evaluate the expression profiles of MUC5AC, FOXA2, and ST3GAL4. Additionally, mice overexpressing FOXA2 were generated to assess pulmonary inflammation, mucus secretion, and related protein expression following PAO1 exposure. In vitro, a model of mucus hypersecretion was induced in NCI-H292 cells using pyocyanin (PCN) to measure the expression levels of FOXA2, ST3GAL4, and MUC5AC and to elucidate their potential interactions. Results from both in vivo and in vitro experiments demonstrated that FOXA2 overexpression significantly inhibited the expression of ST3GAL4 and MUC5AC, thereby alleviating pulmonary pathological damage. Mechanistically, FOXA2 overexpression effectively suppressed the ERK/NF-κB signaling pathway, while pharmacological inhibition of ERK significantly reduced MUC5AC expression. Collectively, these findings suggest that FOXA2 mitigates airway mucus hypersecretion by downregulating ST3GAL4 through modulation of the ERK/NF-κB signaling pathway.