Gata3 drives miR-21-5p transcription to mitigate hyperoxia-induced lung injury, independent of CpG Island methylation.

microRNA-21-5p (miR-21-5p) plays a key anti-apoptotic role in hyperoxia-induced lung injury (HALI), but its regulatory mechanisms are not well understood. This study identified Gata3 as a novel upstream transcription factor that enhanced miR-21-5p expression. Bioinformatic analyses and GEO transcriptomic data revealed a positive correlation between Gata3 and miR-21-5p levels. Notably, the miR-21-5p promoter lacked a CpG island, indicating transcriptional regulation independent of methylation. Gata3 promoted miR-21-5p transcription, reduced apoptosis in alveolar epithelial cells and alleviating HALI. Furthermore, Gata3 overexpression failed to mitigate HALI in miR-21-5p knockout mice, highlighting the critical role of miR-21-5p in Gata3-mediated lung protection. This study uncovered a novel transcriptional mechanism for miRNA regulation, providing valuable insights into the pathogenesis of HALI.