Indole‐3‐Propionic Acid Improves Alveolar Development Impairment via Targeting VAMP8‐mediated SNAREs Complex Formation in Bronchopulmonary Dysplasia

ABSTRACT Bronchopulmonary dysplasia (BPD) disrupts the process of alveolar development, characterized by damage to alveolar epithelial type II cells (AEC II). The present study aims to evaluate the impact of the tryptophan‐derived metabolite indole‐3‐propionic acid (IPA) on postnatal pulmonary development in BPD. Metabolomics indicated that tryptophan metabolic dysfunction is associated with BPD, with IPA emerging as a key metabolite that co‐varies at neonatal levels in both clinical and experimental BPD. Supplementation with IPA protected against hyperoxia‐induced alveolar simplification, which was characterized by increased pro‐proliferative, anti‐apoptotic, and pro‐transdifferentiation activities. Mechanistically, we evaluated circular dichroism (CD), molecular docking, surface plasmon resonance (SPR), and immunoprecipitation techniques, and speculated that IPA exerted its inhibitory effect on phosphorylation of vesicle associated membrane protein 8 (VAMP8) through direct molecular binding. This interaction influenced the assembly of the soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor (SNARE) complex and subsequently promotes autophagosome‐lysosome fusion. In summary, IPA alleviates hyperoxia‐induced alveolar arrest by promoting autophagosome‐lysosome fusion via inhibition of VAMP8 phosphorylation, which is suggestive of a promising therapeutic target of BPD.