Metabolic Reprogramming in Periodontitis: Evidence Stratification, Pharmacological Modulators, and Translational Challenges

Periodontitis is a biofilm-associated inflammatory disease in which dysregulated host responses drive progressive destruction of the tooth-supporting tissues. Although recent reviews have emphasized immune-cell or macrophage metabolism, an evidence-stratified narrative synthesis linking local periodontal mechanisms to pharmacological readiness remains lacking. In this narrative review, we evaluate periodontitis-specific evidence for alterations in glucose, lipid and amino-acid metabolism, mitochondrial function and metabolite-mediated signaling, and examine how these processes interact with the AMPK–mTOR, NF-κB–HIF-1α, PI3K/AKT, JAK/STAT and Nrf2/GPX4 pathways. Direct experimental evidence supports HK2- and PKM2-associated glycolytic reprogramming, mitochondrial dysfunction and context-dependent lactate/lactylation signaling in periodontal fibroblasts, macrophages, osteoclasts and periodontal ligament stem cells. However, much of the mechanistic evidence derives from lipopolysaccharide-stimulated cell lines and rodent ligature models, whereas human evidence is dominated by observational transcriptomic and metabolomic studies. Single-cell and spatial transcriptomic studies have revealed marked cellular heterogeneity, but these approaches infer rather than directly measure metabolic flux. Most metabolism-targeted interventions remain preclinical; limited clinical evidence is available for locally delivered metformin, while other small molecules, natural products and nanoplatforms require pharmacokinetic, safety and efficacy validation. By distinguishing direct periodontal evidence from mechanistic extrapolation and by qualitatively appraising therapeutic readiness, this review defines priorities for spatial metabolomics, isotope-tracing studies, externally validated computational models and mechanism-informed clinical trials.