Periodontitis is a chronic inflammatory disease characterized by persistent inflammation that induces senescence and functional impairment of human periodontal ligament stem cells (HPDLSCs), thereby hindering periodontal regeneration. Mitochondrial dysfunction is a key driver of inflammation-induced stem cell senescence. However, the signaling mechanisms remain unclear. In this study, we examined whether α-ketoglutarate (α-KG), a vital intermediate in the tricarboxylic acid cycle, could alleviate mitochondrial dysfunction and restore HPDLSCs function in inflammatory environments. In vitro experiments demonstrated that lipopolysaccharide (LPS) exposure led to a loss of mitochondrial membrane potential, excessive accumulation of mitochondrial reactive oxygen species, cellular senescence, and impaired osteogenic differentiation in HPDLSCs. Treatment with α-KG significantly restored mitochondrial homeostasis, decreased senescence-associated β-galactosidase activity and the expression of P16 and P53, and enhanced osteogenic differentiation. Mechanistically, α-KG markedly activated AMP-activated protein kinase (AMPK) signaling, while pharmacological inhibition of AMPK negated the protective effects of α-KG on mitochondrial function, senescence, and osteogenesis. Further analysis revealed that α-KG restored the expression of liver kinase B1 (LKB1), a key upstream activator of AMPK, establishing an α-KG/LKB1-AMPK signaling axis in the periodontitis inflammatory microenvironment. In a ligature-induced rat model of periodontitis, oral administration of α-KG mitigated alveolar bone loss, reduced the expression of senescence-associated markers, restored AMPK signaling in periodontal tissues, and promoted periodontal regeneration in vivo. Collectively, these findings reveal that AMPK-dependent mitochondrial restoration is a critical mechanism through which α-KG counteracts inflammation-induced HPDLSCs senescence and osteogenic dysfunction, suggesting that α-KG may serve as a promising therapeutic strategy for periodontal regeneration in inflammatory contexts.
