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...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
KeAi Communications Co., Ltd.
2025-12-01
|
| Series: | Non-coding RNA Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2468054025000769 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849254294367240192 |
|---|---|
| author | Yina Li Nan Wang Jinying Hu Minlan Luo Na Zhang Lili Gao |
| author_facet | Yina Li Nan Wang Jinying Hu Minlan Luo Na Zhang Lili Gao |
| author_sort | Yina Li |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-06eb2f88a712473aa04ba32affbe9d1a |
| institution | Kabale University |
| issn | 2468-0540 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Non-coding RNA Research |
| spelling | doaj-art-06eb2f88a712473aa04ba32affbe9d1a2025-08-20T03:56:04ZengKeAi Communications Co., Ltd.Non-coding RNA Research2468-05402025-12-0115516410.1016/j.ncrna.2025.07.001The mechanism of plasma exosome miR-15a-5p targeting the CF-modified protein IGF1R to regulate alveolar epithelial autophagy and influence pulmonary interstitial fibrosisYina Li0Nan Wang1Jinying Hu2Minlan Luo3Na Zhang4Lili Gao5Department of Respiratory Medicine, The First Affliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of ChinaDepartment of Respiratory Medicine, The First Affliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of ChinaDepartment of Respiratory Medicine, The First Affliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of ChinaDepartment of Respiratory Medicine, The First Affliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of ChinaCorresponding author. The First Affliated Hospital of Dalian Medical University, NO. 222, Zhongshan Road, Xigang District, Dalian City, Liaoning Province, People's Republic of China.; Department of Respiratory Medicine, The First Affliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of ChinaCorresponding author. The First Affliated Hospital of Dalian Medical University, NO. 222, Zhongshan Road, Xigang District, Dalian City, Liaoning Province, People's Republic of China.; Department of Respiratory Medicine, The First Affliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of ChinaAims: 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.http://www.sciencedirect.com/science/article/pii/S2468054025000769Pulmonary interstitial fibrosisExosomesAutophagymiRNACore fucosylation |
| spellingShingle | Yina Li Nan Wang Jinying Hu Minlan Luo Na Zhang Lili Gao The mechanism of plasma exosome miR-15a-5p targeting the CF-modified protein IGF1R to regulate alveolar epithelial autophagy and influence pulmonary interstitial fibrosis Non-coding RNA Research Pulmonary interstitial fibrosis Exosomes Autophagy miRNA Core fucosylation |
| title | The mechanism of plasma exosome miR-15a-5p targeting the CF-modified protein IGF1R to regulate alveolar epithelial autophagy and influence pulmonary interstitial fibrosis |
| title_full | The mechanism of plasma exosome miR-15a-5p targeting the CF-modified protein IGF1R to regulate alveolar epithelial autophagy and influence pulmonary interstitial fibrosis |
| title_fullStr | The mechanism of plasma exosome miR-15a-5p targeting the CF-modified protein IGF1R to regulate alveolar epithelial autophagy and influence pulmonary interstitial fibrosis |
| title_full_unstemmed | The mechanism of plasma exosome miR-15a-5p targeting the CF-modified protein IGF1R to regulate alveolar epithelial autophagy and influence pulmonary interstitial fibrosis |
| title_short | The mechanism of plasma exosome miR-15a-5p targeting the CF-modified protein IGF1R to regulate alveolar epithelial autophagy and influence pulmonary interstitial fibrosis |
| title_sort | mechanism of plasma exosome mir 15a 5p targeting the cf modified protein igf1r to regulate alveolar epithelial autophagy and influence pulmonary interstitial fibrosis |
| topic | Pulmonary interstitial fibrosis Exosomes Autophagy miRNA Core fucosylation |
| url | http://www.sciencedirect.com/science/article/pii/S2468054025000769 |
| work_keys_str_mv | AT yinali themechanismofplasmaexosomemir15a5ptargetingthecfmodifiedproteinigf1rtoregulatealveolarepithelialautophagyandinfluencepulmonaryinterstitialfibrosis AT nanwang themechanismofplasmaexosomemir15a5ptargetingthecfmodifiedproteinigf1rtoregulatealveolarepithelialautophagyandinfluencepulmonaryinterstitialfibrosis AT jinyinghu themechanismofplasmaexosomemir15a5ptargetingthecfmodifiedproteinigf1rtoregulatealveolarepithelialautophagyandinfluencepulmonaryinterstitialfibrosis AT minlanluo themechanismofplasmaexosomemir15a5ptargetingthecfmodifiedproteinigf1rtoregulatealveolarepithelialautophagyandinfluencepulmonaryinterstitialfibrosis AT nazhang themechanismofplasmaexosomemir15a5ptargetingthecfmodifiedproteinigf1rtoregulatealveolarepithelialautophagyandinfluencepulmonaryinterstitialfibrosis AT liligao themechanismofplasmaexosomemir15a5ptargetingthecfmodifiedproteinigf1rtoregulatealveolarepithelialautophagyandinfluencepulmonaryinterstitialfibrosis AT yinali mechanismofplasmaexosomemir15a5ptargetingthecfmodifiedproteinigf1rtoregulatealveolarepithelialautophagyandinfluencepulmonaryinterstitialfibrosis AT nanwang mechanismofplasmaexosomemir15a5ptargetingthecfmodifiedproteinigf1rtoregulatealveolarepithelialautophagyandinfluencepulmonaryinterstitialfibrosis AT jinyinghu mechanismofplasmaexosomemir15a5ptargetingthecfmodifiedproteinigf1rtoregulatealveolarepithelialautophagyandinfluencepulmonaryinterstitialfibrosis AT minlanluo mechanismofplasmaexosomemir15a5ptargetingthecfmodifiedproteinigf1rtoregulatealveolarepithelialautophagyandinfluencepulmonaryinterstitialfibrosis AT nazhang mechanismofplasmaexosomemir15a5ptargetingthecfmodifiedproteinigf1rtoregulatealveolarepithelialautophagyandinfluencepulmonaryinterstitialfibrosis AT liligao mechanismofplasmaexosomemir15a5ptargetingthecfmodifiedproteinigf1rtoregulatealveolarepithelialautophagyandinfluencepulmonaryinterstitialfibrosis |