METTL14-mediated mA modification of DDIT4 promotes its mRNA stability in aging-related idiopathic pulmonary fibrosis.

Although N-methyladenosine (mA) may be related to the pathogenesis of fibrotic process, the mechanism of mA modification in aging-related idiopathic pulmonary fibrosis (IPF) remains unclear. Three-milliliter venous blood was collected from IPF patients and healthy controls. MeRIP-seq and RNA-seq were utilized to investigate differential mA modification. The expressions of identified mA regulator and target gene were validated using MeRIP-qPCR and real-time PCR. Moreover, we established an animal model and a senescent model of A549 cells to explore the associated molecular mechanism. Our study provided a panorama of mA methylation in IPF. Increased peaks (3756) and decreased peaks (4712) were observed in the IPF group. The association analysis showed that 749 DEGs were affected by mA methylation in IPF. Among the mA regulators, the expression of METTL14 decreased in IPF. The mA level of our interested gene DDIT4 decreased significantly, but the mRNA level of DDIT4 was higher in IPF. This was further verified in bleomycin-induced pulmonary fibrosis. At the cellular level, it was further confirmed that METTL14 and DDIT4 might participate in the senescence of alveolar epithelial cells. The downregulation of METTL14 might inhibit the decay of DDIT4 mRNA by reducing the mA modification level of DDIT4 mRNA, leading to high expression of DDIT4 mRNA and protein. Our study provided a panorama of mA alterations in IPF and discovered METTL14 as a potential intervention target for epigenetic modification in IPF. These results pave the way for future investigations regarding mA modifications in aging-related IPF.