The mechanism of plasma exosome miR-15a-5p targeting the CF-modified protein IGF1R to regulate alveolar epithelial autophagy and influence pulmonary interstitial fibrosis.

AIMS

This study investigates how plasma exosomal miRNAs regulate core fucosylation (CF)-modified targets to influence autophagy and fibrosis in idiopathic pulmonary fibrosis (IPF), aiming to identify novel therapeutic strategies targeting dysregulated alveolar epithelial cell (AEC) autophagy.

MATERIALS AND METHODS

Plasma exosomes from IPF patients and healthy controls were isolated via ultracentrifugation, validated by TEM, nanoparticle tracking analysis (NTA), and Western blot (CD9/CD81). Exosomal miRNA profiling employed high-throughput sequencing, with TargetScan/miRanda predicting target genes. A549 and MLE-12 cells assessed exosome uptake (PKH67 labeling) and miRNA-mRNA interactions (dual-luciferase assays). CF modification was analyzed via immunoprecipitation/Western blot. In vivo validation used bleomycin (BLM)-induced fibrosis models in alveolar epithelial-specific FUT8-knockout (CKO) mice.

KEY FINDINGS

IPF plasma exosomes suppressed autophagy and exacerbated fibrosis in AECs. miR-15a-5p was markedly downregulated in IPF exosomes. Overexpression of miR-15a-5p reversed BLM-induced autophagy inhibition and fibrosis. Mechanistically, miR-15a-5p directly targeted IGF1R, a CF-modified protein. Reduced miR-15a-5p elevated IGF1R expression, activating PI3K/AKT to inhibit autophagy and promote fibrosis.

SIGNIFICANCE

This study identifies miR-15a-5p as a critical regulator of CF-modified IGF1R in IPF pathogenesis. Its downregulation drives PI3K/AKT-mediated autophagy suppression, accelerating fibrosis. Restoring miR-15a-5p or targeting IGF1R/PI3K/AKT signaling may offer novel therapeutic avenues for IPF.