METTL14 ‐Mediated m6A Modification of NEAT1_2 Releases YBX1 From Paraspeckles to Exacerbate Periodontitis

Aim To investigate the role and epigenetic mechanism of methyltransferase 14 (METTL14)‐mediated N6‐adenylate methylation (m6A) modification of long non‐coding RNAs (lncRNAs) in the pathogenesis of periodontitis. Materials and Methods A periodontal ligament–targeted Mettl14 ‐cKO mouse model ( Gli1‐Cre ERT2 ;Mettl14 fl/fl ) was established using silk ligatures. Human periodontal ligament cells (PDLCs) were used for in vitro assays. MeRIP‐seq, RNA‐seq, RNA pull‐down, mass spectrometry, RIP Co‐IP and CUT&Tag were performed to elucidate the METTL14–NEAT1_2–YBX1 axis. Results METTL14 expression was significantly up‐regulated in inflamed periodontal tissue. METTL14 deficiency alleviated alveolar bone destruction and suppressed IL‐6 expression in vivo and in vitro. Mechanistically, METTL14 catalysed m6A modification of nuclear paraspeckle assembly transcript 1_2 (NEAT1_2), facilitating NEAT1_2 degradation. NEAT1_2‐organised paraspeckles (PSPs) sequestered the transcription factor Y‐box binding protein 1 (YBX1) under normal conditions. In periodontitis, METTL14‐induced NEAT1_2 down‐regulation triggered PSP disassembly, resulting in the translocation of YBX1 to the nucleus and increased IL‐6 transcription. Neat1_2 knockdown exacerbated bone loss and neutralised the protective effect of METTL14 deficiency. Conclusion METTL14‐mediated m6A modification exacerbates periodontitis by disrupting NEAT1_2‐dependent PSP sequestration of YBX1. This study identifies the METTL14–NEAT1_2 axis as a critical regulator of periodontal inflammation, suggesting that METTL14 is a potential therapeutic target for periodontitis.