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

Summary

This study identifies CEPT1 downregulation in asthmatic airway epithelium as a driver of phospholipid imbalance, activating all three ER stress pathways, disrupting ER Ca2+ homeostasis, and promoting mitochondrial dysfunction. The work delineates a FOXA1–CEPT1 axis linking lipid metabolism to epithelial stress responses, offering therapeutic entry points to restore membrane phospholipids and attenuate inflammation.

Key Findings

• CEPT1, a key phospholipid biosynthetic enzyme, is significantly downregulated in asthmatic airway epithelium.
• CEPT1 deficiency reduces PC/PE, induces phospholipid imbalance, activates all three ER stress branches, and disrupts ER Ca2+ homeostasis.
• Mitochondrial dysfunction accompanies ER stress, linking epithelial metabolic defects to asthma pathophysiology.
• FOXA1 is implicated in regulating CEPT1, establishing a FOXA1–CEPT1 mechanistic axis.

Clinical Implications

Therapies that restore phosphatidylcholine balance or upregulate CEPT1, and interventions targeting ER stress/mitochondrial resilience, could reduce epithelial injury and airway hyperreactivity. CEPT1 expression may stratify patients for precision interventions.

Limitations

• Preclinical mechanistic focus; causal validation in human tissues and clinical cohorts is pending
• Therapeutic reversibility of CEPT1 deficits and safety of lipid restoration strategies remain to be established

Future Directions

Test CEPT1 restoration or phosphatidylcholine supplementation in translational models; evaluate ER stress/mitochondrial protectants; validate CEPT1 as a biomarker in longitudinal asthma cohorts.