Mitochondrial hub: the integrative axis connecting ferroptosis and metabolic reprogramming in periodontitis

Periodontitis is a chronic inflammatory disease characterized by persistent periodontal tissue destruction and alveolar bone loss, which is closely associated with multiple systemic disorders. Emerging evidence indicates that ferroptosis and metabolic reprogramming are jointly involved in the progression of periodontitis; however, their causal linkage, hierarchical regulatory network, and unified core mechanism remain unclear. This review proposes a mitochondria-centered unifying axis that links metabolic reprogramming and ferroptosis in periodontitis. Specifically, periodontal pathogens trigger mitochondrial structural and functional collapse, which in turn drives comprehensive metabolic disturbances covering iron, lipid, amino acid, and glucose metabolism, thereby facilitating ferroptosis. Exacerbated ferroptosis further aggravates mitochondrial damage, forming a self-sustaining pathological vicious cycle that underlies refractory inflammation and sustained alveolar bone resorption. We systematically elaborate the molecular basis of this mitochondria-metabolism-ferroptosis axis and outline a translational framework encompassing mitochondria-targeted therapeutics and advanced nano-delivery systems. This review provides a novel mechanistic basis for addressing therapeutic resistance and frequent recurrence in periodontitis, with profound theoretical value and translational promise for clinical application.