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A novel circRNA-miRNA-mRNA regulatory axis as a sex-specific biological variable in bronchopulmonary dysplasia

Pragnya Das1,2, Sharmishtha Shyamal3, Varsha M Prahaladan1

  • 1Cooper University Hospital, Department of Pediatrics, Camden, NJ 08103, USA.

NAR Molecular Medicine
|November 19, 2025
PubMed

Insights

Bronchopulmonary Dysplasia (BPD) is a severe lung disease in premature infants. Researchers identified circNfix and Ntrk2 as key regulators in BPD's sexual dimorphism, suggesting circNfix GapmeR as a potential therapy.

Area of Science:

  • Neonatal Medicine
  • Pulmonary Biology
  • Molecular Genetics

Background:

  • Bronchopulmonary Dysplasia (BPD) is a severe pulmonary complication in premature infants (<28 weeks gestation) caused by hyperoxia.
  • BPD exhibits sexual dimorphism, with no current curative treatments.
  • MicroRNAs (miRNAs) and circular RNAs (circRNAs) are implicated in BPD pathogenesis and show differential expression between sexes.

Purpose of the Study:

  • To investigate the dimorphism of circRNAs in Bronchopulmonary Dysplasia (BPD).
  • To elucidate a circRNA-miRNA-mRNA regulatory axis in response to hyperoxia.
  • To identify potential therapeutic targets for BPD.

Main Methods:

  • RNA-Sequencing to identify circRNAs in developing lungs under room air (RA) and hyperoxia (BPD) conditions.
  • Analysis of differential circRNA expression between sexes in control and BPD groups.
  • Functional validation using GapmeR to silence circNfix and assess its impact on Ntrk2 expression and alveolar phenotype.

Main Results:

  • Approximately 33,000 circRNAs were identified; a few showed differential expression between sexes in RA and BPD groups.
  • circNfix was identified as a sponge for miR204-5p, targeting the Ntrk2 mRNA.
  • Silencing circNfix suppressed Ntrk2 and improved the alveolar phenotype in male BPD pups.

Conclusions:

  • circNfix and Ntrk2 are proposed as novel key regulators in BPD pathogenesis and sexual dimorphism.
  • The circNfix/miR204-5p/Ntrk2 axis plays a significant role in hyperoxia-induced lung injury.
  • circNfix GapmeR demonstrates potential as a therapeutic strategy for BPD.

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