The impact of m6A methyltransferase <i>METTL3</i> on airway remodeling in bronchial asthma

Methyltransferase-like 3 (<i>METTL3</i>) is known to play a role in asthma airway remodeling and cell proliferation. Adenylate kinase 4 (AK4) regulates the proliferation of pulmonary artery smooth muscle cells and exerts its effects through the protein kinase B (AKT) pathway. However, the role of METTL3 and AK4-AKT in bronchial smooth muscle cells remains unclear. Systemic <i>METTL3</i> knockout mice and a mouse model of asthma were established. Airway remodeling was assessed using pulmonary function tests, histopathological staining, and Western blot analysis. RNA sequencing (RNA-seq) was performed to detect changes in gene expression following <i>METTL3</i> knockdown. The 5-Ethynyl-2'-deoxyuridine (EdU) assay was used to evaluate cell proliferation. Finally, the expression levels of relevant proteins were validated by Western blotting. Compared with the control model group, the <i>METTL3</i> knockout group showed significantly reduced inflammatory cell infiltration, decreased collagen fiber deposition, and attenuated airway smooth muscle hyperplasia. RNA-seq revealed that the expression of numerous proliferation-related genes, including AK4, was upregulated following <i>METTL3</i> knockdown. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that these genes were primarily enriched in the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway. The EdU assay demonstrated that <i>METTL3</i> knockdown inhibited cell proliferation. Western blot validation showed increased AK4 expression in lung tissues of the <i>METTL3</i> knockout group compared to the control group, while phosphorylated AKT (p-AKT) levels were reduced. <i>METTL3</i> knockout inhibits airway smooth muscle hyperplasia and alleviates airway remodeling in asthma. This effect may be mediated through the regulation of AK4 and the AKT signaling pathway.