FOXA1-mediated CEPT1 deficiency in airway epithelium drives asthma via an ER stress-mitochondrial dysfunction axis

Asthma is associated with disordered glycerophospholipid metabolism and decreased phosphatidylcholine (PC), but the molecular basis remains incompletely defined. Through integrative data mining, we identify CEPT1, a key enzyme in glycerophospholipid biosynthesis, to be significantly downregulated in the airway epithelium of asthma. CEPT1 deficiency causes PC/PE reduction and phospholipid imbalance, activates all three endoplasmic reticulum (ER) stress pathways, disturbs ER Ca²⁺ stores, and drives mitochondrial Ca²⁺ overload, which in turn triggers mitochondrial oxidative stress. Notably, administration of polyenylphosphatidylcholine (PPC) restores ER and mitochondrial homeostasis and reduces apoptosis, cytokine release, and mucus overproduction. FOXA1 is identified as a direct transcriptional activator of CEPT1. In vivo, CEPT1 overexpression alleviates airway inflammation and mucus hypersecretion. Collectively, our study elucidates an axis wherein FOXA1-mediated CEPT1 repression induces ER stress and mitochondrial dysfunction through disrupted calcium handling, driving mucin hypersecretion and airway inflammation-identifying CEPT1 restoration or PPC as potential mechanism-based interventions for asthma.