LOR Regulated by METTL3 Alleviates Lipopolysaccharides-Induced Periodontitis Injury.

Periodontitis is a chronic inflammatory disease-causing tissue destruction and systemic effects. Despite significant advancements, the molecular mechanisms driving tissue degeneration remain incompletely understood. Emerging evidence suggests that RNA modifications, particularly N6-methyladenosine (m⁶A) methylation, critically regulate inflammatory responses. This study investigates the role of METTL3-mediated m⁶A modification of loricrin (LOR) in lipopolysaccharide (LPS)-induced periodontal injury. Bioinformatics analyses identified the key downregulated gene in periodontitis. To establish an in vitro periodontitis model, human periodontal ligament fibroblast (HPLF) cells were treated with LPS. LOR and METTL3 levels in clinical samples and HPLF cells were measured by qRT-PCR. Inflammatory cytokines, cell proliferation, and apoptosis were examined using ELISA, CCK8, EdU, and flow cytometry assays, respectively. The interaction between LOR and METTL3 was evaluated through Pearson correlation, MeRIP assay, qRT-PCR, immunoblotting, and mRNA stability assays. LOR was identified as a key downregulated gene in periodontitis, as validated in both clinical tissues and a periodontitis cell model. Functional assays showed that LPS-treatment promoted inflammatory cytokine production, inhibited cell proliferation, and increased apoptosis, whereas upregulating LOR in these cells reversed these effects. Furthermore, METTL3 expression was reduced in periodontitis clinical tissues and positively correlated with LOR expression. METTL3 overexpression enhanced LOR mRNA stability via m⁶A methylation. Moreover, silencing METTL3 partially negated the protective effects of LOR overexpression in LPS-induced periodontitis cell model. These findings reveal that METTL3-mediated m⁶A modification of LOR mitigates periodontal injury, suggesting that the METTL3-LOR axis may represent a potential avenue for future therapeutic exploration to maintain periodontal homeostasis.