Palmitic acid aggravates airway inflammation in asthma through induction of chemokines expression and metabolomic changes in epithelial cells

BACKGROUND: Elevated palmitic acid (PA) levels have been associated with increased asthma risk, but its pathogenic role remains unclear. This study aims to investigate the relationship between serum PA levels and asthma severity and explores the pro-inflammatory effects of PA on airway epithelial cells and the underlying mechanism. METHODS: Serum samples were collected from asthmatic patients, and the concentrations of PA were quantified by ELISA. An HDM-induced mouse model of asthma was established and treated with PA. RNA sequencing and metabolomic profiling were used to identify PA-responsive genes and metabolites in airway epithelial cells, and key targets were validated by qPCR, Western blot, and ELISA. RESULTS: We found that elevated serum PA levels correlated with worse lung function, higher blood neutrophil percentages, and increased steroid needs in asthma patients. In a murine asthma model, PA exacerbated airway inflammation, hyperresponsiveness, and neutrophil infiltration. In vitro, PA stimulated airway epithelial cells to express high levels of neutrophil chemokines (CXCL2/CXCL8) via Src-ERK pathway activation. In addition, metabolomic analyses revealed that PA triggered pro-inflammatory metabolic reprogramming in airway epithelial cells, characterized by dysregulation of acylcarnitine/fatty acid β-oxidation, sphingolipid signaling, and arachidonic acid metabolism. Using of CD36 inhibitors significantly suppressed pro-inflammatory chemokines expression, Src/ERK signaling activation, and metabolic reprogramming in airway epithelial cells, as well as in the asthma mouse model. CONCLUSIONS: our study demonstrated elevated PA exacerbates airway inflammation in asthma by inducing neutrophil chemokine expression and metabolic reprogramming in airway epithelial cells, providing novel insights into the pathophysiology of metabolically dysregulated asthma.