Hyperglycemia disrupts alveolar bone homeostasis by inducing stem cell senescence through Mettl3/Foxo3/Sirt1 axis in diabetic periodontitis

AIMS: Diabetes exacerbates periodontitis by intensifying inflammatory responses and impairing tissue regeneration. Hyperglycemia-induced dysfunction of jawbone-derived bone marrow mesenchymal stem cells (BMSCs) contributes to the imbalance of bone remodeling and periodontal homeostasis. This study aimed to reveal the role and regulatory mechanism of stem cell senescence in diabetic periodontitis. MATERIALS AND METHODS: Diabetic periodontitis model was established in mice by high-fat diet, streptozotocin injections and ligation. Following treatment with high glucose (HG) and Porphyromonas gingivalis lipopolysaccharide (Pg-LPS), BMSCs were analyzed for cellular senescence and m⁶A levels. Functional roles of Mettl3, Foxo3, and Sirt1 were explored by knockdown, overexpression, and pharmacological activation. MeRIP, ChIP, and RNA stability assays were employed to explore m⁶A-dependent Foxo3 degradation and its interaction with Sirt1. Therapeutic potential of Sirt1 activation was validated in vivo. KEY FINDINGS: Diabetic mice developed alveolar bone degeneration and cellular senescence pathway enrichment. HG + LPS co-stimulation induced BMSCs senescence, elevated m⁶A levels and Mettl3 expression. Mettl3 knockdown reduced senescence-associated secretory phenotypes. Mechanistically, m⁶A hypermodification on the Foxo3 coding sequence accelerated mRNA decay and impeded nuclear translocation via Ythdf2 recognition. Through its transcriptional regulation of Sirt1, Foxo3 mitigated senescence when overexpressed and exacerbated oxidative damage when knocked down. Sirt1 activation alleviated senescence in vitro and in vivo, reciprocally stabilizing Foxo3 and maintaining its transcriptional activity via deacetylation. SIGNIFICANCE: Hyperglycemia disrupts alveolar bone homeostasis by driving stem cell senescence through the Mettl3/Foxo3/Sirt1 axis, suggesting a promising therapeutic strategy for regenerative therapy under diabetic conditions.