Wildfire Smoke Remodels the Phosphoproteome of Airway Epithelial Cells to Disrupt Cilia Function and Barrier Integrity

The airway epithelium protects the body through tight barrier function and coordinated mucociliary clearance, yet how wildfire smoke disrupts these defenses remains poorly understood. Here, we analyzed upper airway tissue from individuals exposed to the 2025 Los Angeles wildfires and observed epithelial barrier disruption and the intracellular accumulation of fine and ultrafine particulate structures. Using a controlled wood combustion exposure system in primary human airway epithelial cultures differentiated at the air–liquid interface, we show that wood-fire smoke rapidly impairs barrier integrity and arrests ciliary beating without widespread cell loss. Integrated transcriptomic, proteomic, and phosphoproteomic analyses revealed the suppression of ciliary and cytoskeletal gene programs together with extensive remodeling of phosphorylation across proteins that regulate ciliary structure, cytoskeletal organization, and epithelial junctions. This was confirmed by functional studies showing severe impairment of ciliary movement and a loss of airway transepithelial electrical resistance (TEER). ERK pathway activation emerged as a dominant kinase response to wood-fire smoke, and pharmacologic inhibition of MEK restored phosphorylation patterns, preserved epithelial barrier integrity, and protected ciliary motility. Transmission electron microscopy confirmed ultrastructural changes in cilia induced by wood-fire smoke that were prevented by MEK inhibition. Together, these findings identify phosphorylation remodeling as a preventable mechanism of injury following wildfire smoke exposure and establish ERK signaling as a tractable therapeutic target for protecting the airway function.