METTL14 Inhibits the Pyroptosis of Neurons in Parkinson's Disease via Upregulating NFE2

Methyltransferase-like 14 (METTL14) has been identified as a protective factor in central nervous system disorders, yet its involvement in Parkinson's disease (PD) remains underexplored. This study aimed to investigate the role of METTL14 in PD. An in vitro PD model was established by exposing neurons to 1-methyl-4-phenylpyridinium (MPP+). mRNA levels were quantified via real-time-quantitative PCR. Protein expression was assessed through Western blot. The release of pyroptosis-related cytokines was detected using enzyme-linked immunosorbent assay. N6-methyladenosine (m6A) levels were measured using an m6A assay. m6A enrichment was pinpointed with a methylated RNA immunoprecipitation assay. The transcriptional activity of nuclear factor, erythroid 2 (NFE2) was evaluated using a luciferase assay. Cell viability, neuronal cytotoxicity, and neuronal death were respectively determined using Cell Counting Kit-8, lactate dehydrogenase, and terminal deoxynucleotidyl transferase dUTP nick-end labeling assays. Our findings unveiled that METTL14 expression is diminished following MPP+ exposure, which in turn triggers neuroinflammation and pyroptosis. Conversely, overexpression of METTL14 mitigates neuroinflammation and pyroptosis, and restores neuronal function. Mechanistically, METTL14 augments the m6A modification of NFE2 at a specific site, thereby preserving its mRNA stability. However, NFE2 knockdown exacerbates neuroinflammation and pyroptosis. In summary, METTL14 safeguards against neurodegeneration in PD by modulating the m6A modification of NFE2, positioning the METTL14/NFE2 axis as a potential therapeutic target for PD.