METTL3 Promotes Lipid Deposition and Pulmonary Fibrosis by Destabilizing PLIN2 in a m6A-Dependent Manner.

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disorder that is associated with aberrant lipid metabolism. N6-methyladenosine (m6A) methylation is involved in IPF progression. However, whether METTL3, a m6A methyltransferase, modulates lipid metabolism in IPF remains unknown. In this study, we aimed to investigate the effects of METTL3 on fibrosis and lipid accumulation and identify the molecular mechanism. PF mouse model was generated by bleomycin. WI-38 cells were stimulated with TGF-β1 to mimic the IPF-caused damage. Lipids were observed using Nile Red staining and marker detection. Fibrosis was evaluated using Masson's Trichrome staining and marker detection. The molecular mechanism was analysed by methylated RNA immunoprecipitation and dual-luciferase reporter assay. We found that METTL3 is highly expressed in IPF mice and TGF-β1-induced WI-38 cells. Knockdown of METTL3 inhibited lipid accumulation and fibrosis In Vitro and In Vivo. Additionally, interference with METTL3 suppressed the m6A methylation of PLIN2, enhanced its stability, and increased its expression. Knockdown of PLIN2 reversed the inhibition of lipid accumulation and fibrosis caused by METTL3 silence. In conclusion, interfering with METTL3 attenuates IPF progression by suppressing lipid deposition, which is associated with the increased stability of PLIN2 suggesting a promising therapeutic target for IPF.