2. Academic Validation
  3. Extracellular vesicle-mediated transcellular mitophagy as a modulatory target for moderate hyperoxia-induced alveolar developmental arrest in bronchopulmonary dysplasia

Extracellular vesicle-mediated transcellular mitophagy as a modulatory target for moderate hyperoxia-induced alveolar developmental arrest in bronchopulmonary dysplasia

  • Free Radic Biol Med. 2026 Jun:249:453-468. doi: 10.1016/j.freeradbiomed.2026.03.035.
Yifan Sun 1,  Tengfei Wang 2,  Yun Yang 3,  Rui Wang 2,  Bowen Zhu 2,  Jinya Wang 4,  Gaoli Liang 4,  Wei Peng 2,  Na Zhang 2,  Xirong Guo 5,  Xingyun Wang 6
Affiliations

Affiliations

  • 1 Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China; Department of Neonatology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200062, China.
  • 2 Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China.
  • 3 Department of Child Health Care, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China.
  • 4 Department of Pediatrics, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, 210008, China.
  • 5 Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China. Electronic address: [email protected].
  • 6 Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China; Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, 510000, China. Electronic address: [email protected].
PMID: 41833585 DOI: 10.1016/j.freeradbiomed.2026.03.035
Abstract

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.

Keywords

Alveolar developmental arrest; Fibroblast-derived extracellular vesicles; Mitochondrial transfer; Mitophagy; Outer mitochondrial membrane.

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