Oxygen therapy is required for the survival of premature infants with respiratory distress, yet hyperoxia exposure is a major contributor to alveolar developmental arrest in bronchopulmonary dysplasia (BPD). Despite the recognized role of fibroblasts in lung development, their functional contributions to the alveolar niche under hyperoxia remain poorly defined. Here, we profiled the involvement of fibroblasts using a BPD model induced by moderate hyperoxia (60% oxygen). Single-cell RNA sequencing (scRNA-seq) revealed that fibroblasts transitioned toward a disease-associated phenotype and exhibited enhanced communication with type II alveolar epithelial cells (AEC IIs) under moderate hyperoxia. Furthermore, activated fibroblasts increased the susceptibility of AEC IIs to hyperoxia via extracellular vesicles (EVs). These EVs were enriched with mitochondrial components, particularly the outer mitochondrial membrane (OMM) protein VDAC1. OMM-enriched EVs inhibited BNIP3-dependent mitophagy initiation in AEC IIs via VDAC1-GCN2 complex formation, leading to autophagic flux blockade and mitochondrial dysfunction. Inhibition of fibroblast-derived EV release using GW4869 or administration of human umbilical cord mesenchymal stem cell (hUC-MSC)-derived EVs attenuated hyperoxia-induced AEC II dysfunction and alveolar structural impairment. Taken together, our findings identify a fibroblast-epithelial communication mechanism that impairs mitochondrial homeostasis and leads to alveolar developmental arrest, highlighting a promising therapeutic target for BPD. • Activated fibroblasts sensitize AEC IIs to hyperoxia via EVs. • Fibroblast-derived EVs deliver VDAC1 to AEC IIs under moderate hyperoxia. • EV-mediated transfer of VDAC1 inhibits BNIP3-dependent mitophagy in AEC IIs. • Suppression of fibroblast-EV release alleviates alveolar developmental arrest. • hUC-MSC-derived EVs restore AEC II function and alveolar structure in BPD models.
Sun et al. (2026) studied this question.