Mitochondrial DNA driven senescence-associated secretory phenotype facilitates the development of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is characterized by arrested alveolar development and disrupted vascular growth in preterm infants. While cellular senescence has been well established in age-related diseases, such as chronic lung diseases, its role in developmental lung diseases originating in the neonatal period remains largely unknown. Here, we investigated the role and underlying mechanisms of the senescence-associated secretory phenotype (SASP) in BPD using targeted inhibitor treatments and rescue strategies. Key SASP factors, including IL-6, IL-1β, MMP-12, and TGF-β 1 , were significantly elevated after hyperoxia exposure, indicating their involvement in BPD pathogenesis. Confocal imaging revealed that hyperoxia-induced partial mitochondrial outer membrane permeabilization triggered mitochondrial DNA (mtDNA) leakage, establishing mitochondrial dysfunction as a key driver of BPD progression. Further experiments demonstrated the role of the voltage-dependent anion channel 1 (VDAC1) oligomerization and the cGAS-STING pathway in mediating mtDNA release and SASP, respectively. Collectively, these findings define a molecular cascade where VDAC1 oligomerization causes mtDNA leakage, activating cGAS-STING to drive SASP during BPD progression. Targeting the cGAS-STING pathway holds therapeutic potential for alleviating the chronic impact of BPD.