Bronchopulmonary Dysplasia Starts in Utero: MicroRNA Dysregulation Across the Fetal–Neonatal Continuum in the Bronchopulmonary Dysplasia Development

ABSTRACT

Bronchopulmonary dysplasia (BPD) is a heterogeneous developmental lung disorder resulting from the interaction between antenatal susceptibility and postnatal injury. Increasing evidence suggests that its biological origins may precede preterm birth, with placental dysfunction, fetal growth restriction, inflammation and oxidative stress influencing pulmonary developmental trajectories before exposure to the extrauterine environment. MicroRNAs (miRNAs), small non‐coding RNAs that regulate gene expression at the post‐transcriptional level, are emerging as potential molecular mediators linking these fetal and neonatal processes. This educational review examines miRNA dysregulation across the fetal–neonatal continuum of BPD. We first discuss the role of miRNAs in physiological lung development and their disruption following premature birth. We then explore how placental dysfunction and fetal growth restriction may influence miRNA networks, including placenta‐enriched C19MC miRNAs, thereby contributing to antenatal susceptibility to BPD. Particular attention is given to miRNA‐mediated regulation of pulmonary angiogenesis and VEGF signaling and to the bidirectional relationship between miRNAs and oxidative stress, including modulation of NRF2‐dependent antioxidant responses. Beyond their mechanistic relevance, miRNAs offer potential translational opportunities. Their stability and detectability across different biological compartments—including placenta, cord blood, peripheral blood, respiratory samples and extracellular vesicles—make them attractive candidates for longitudinal biomarker profiling, while experimental modulation using miRNA mimics and inhibitors provides proof of concept for future therapeutic approaches. However, heterogeneity in biological sampling, analytical methods, developmental timing and BPD phenotypes, together with challenges in tissue‐specific delivery and off‐target effects, currently limit clinical translation. Rather than identifying a single ‘BPD miRNA’, future research should focus on dynamic, multi‐compartment miRNA networks integrating antenatal programming with postnatal exposures. Such an approach may improve molecular endotyping, early risk stratification and ultimately the development of individualized preventive and therapeutic strategies for BPD.