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

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. Mater...

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Bibliographic Details
Main Authors: Yina Li, Nan Wang, Jinying Hu, Minlan Luo, Na Zhang, Lili Gao
Format: Article
Language:English
Published: KeAi Communications Co., Ltd. 2025-12-01
Series:Non-coding RNA Research
Subjects:
Pulmonary interstitial fibrosis
Exosomes
Autophagy
miRNA
Core fucosylation
Online Access:http://www.sciencedirect.com/science/article/pii/S2468054025000769
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Summary: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.
ISSN:2468-0540

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