Related Experiment Video
Updated: May 20, 2025
Bronchoalveolar Lavage Exosomes in Lipopolysaccharide-induced Septic Lung Injury
Published on: May 21, 2018
METTL3-mediated m6A Modification Promotes miR-221-3p Expression to Exacerbate Ischemia/Reperfusion-Induced Acute Lung
Yang Yang1, Chenlu Li2, Ziwang Lu3
1Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Abstract:
Ischemia/reperfusion (I/R)-induced acute lung injury (ALI) represents a prevalent pulmonary pathology. The N6-methyladenosine (m6A) RNA modification is integral in regulating numerous biological processes across various human diseases through the modulation of gene expression. Nevertheless, the precise role and underlying molecular mechanisms of m6A modifications in ALI remain inadequately understood. This study aimed to elucidate the impact of RNA methyltransferase 3 (METTL3)-mediated m6A modification of miR-221-3p on the progression of I/R-induced ALI. Our initial findings demonstrated an upregulation of m6A levels and METTL3 expression in I/R-induced ALI in murine models and hypoxia/reoxygenation (H/R)-induced murine lung epithelial (MLE)-12 cells. Inhibition of METTL3 was observed to reverse H/R-induced apoptotic cell death, oxidative stress, and inflammatory cytokine secretion. Furthermore, METTL3 was found to enhance the expression of miR-221-3p in an m6A-dependent manner, thereby contributing to ALI pathogenesis. In addition, miR-221-3p was shown to negatively regulate PTEN expression, while METTL3 facilitated phosphorylated AKT expression via the miR-221-3p/PTEN axis. Functional experiments further revealed that the downregulation of PTEN negated the inhibitory effects of METTL3 knockdown in H/R-treated MLE-12 cells. In conclusion, our study demonstrates that the METTL3-mediated m6A modification of miR-221-3p exacerbates ALI through modulation of the PTEN/AKT pathway. Therapeutic strategies aimed at targeting the METTL3/m6A/miR-221-3p/PTEN/AKT axis may offer a promising approach to mitigate I/R-induced ALI.
Insights
RNA methyltransferase 3 (METTL3) enhances acute lung injury (ALI) by modifying miR-221-3p. This epigenetic modification promotes cell death and inflammation via the PTEN/AKT pathway, offering potential therapeutic targets for ALI.
Area of Science:
- Pulmonary Medicine
- Molecular Biology
- Epigenetics
Background:
- Ischemia/reperfusion (I/R)-induced acute lung injury (ALI) is a significant clinical challenge.
- N6-methyladenosine (m6A) RNA modification regulates gene expression in various diseases, but its role in ALI is unclear.
- Understanding the molecular mechanisms of m6A in ALI is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of METTL3-mediated m6A modification of miR-221-3p in I/R-induced ALI.
- To elucidate the underlying molecular mechanisms involving the PTEN/AKT pathway.
Main Methods:
- Murine models of I/R-induced ALI and hypoxia/reoxygenation (H/R)-induced MLE-12 cells were used.
- Expression levels of m6A, METTL3, and miR-221-3p were analyzed.
- The regulatory effects of METTL3 and miR-221-3p on PTEN and AKT phosphorylation were examined.
Main Results:
- METTL3 and m6A levels were upregulated in ALI models.
- METTL3 inhibition reduced H/R-induced apoptosis, oxidative stress, and inflammation.
- METTL3 promoted miR-221-3p expression in an m6A-dependent manner, exacerbating ALI.
- miR-221-3p targeted PTEN, and METTL3 facilitated p-AKT via the miR-221-3p/PTEN axis.
Conclusions:
- METTL3-mediated m6A modification of miR-221-3p exacerbates ALI by regulating the PTEN/AKT pathway.
- Targeting the METTL3/m6A/miR-221-3p/PTEN/AKT axis presents a potential therapeutic strategy for I/R-induced ALI.
