Investigating the Role of Long Non-Coding RNA HAGLR and Its Target NT5E in Alveolar Epithelial Injury

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by alveolar epithelial injury and fibrosis. Alveolar epithelial type 2 cells (AEC2s) transdifferentiate into basal cells via intermediate states, contributing to disease progression. Long non-coding RNAs (lncRNAs) regulate various cellular processes and gene expression, presenting potential therapeutic targets, but their role in inflammation-induced alveolar injury remains unclear. This study aimed to investigate the expression of lncRNAs in alveolar epithelial injury models relevant to IPF. Using human alveolar epithelial organoids, we identified the lncRNA HAGLR as highly expressed in normal epithelium but markedly reduced following inflammatory stimulation. This downregulation was confirmed in vitro and in IPF lung tissues. NT5E, an immune-regulatory gene, was identified as a downstream target negatively regulated by HAGLR. HAGLR knockdown increased NT5E expression, while overexpression reversed it. NT5E was elevated in fibrotic regions of IPF lungs, where HAGLR was diminished, suggesting an inverse regulatory relationship. These findings indicate that HAGLR modulates alveolar injury responses via NT5E and may serve as a therapeutic target. Targeting the HAGLR-NT5E axis could offer a novel strategy to mitigate fibrosis and respiratory decline in IPF.