The macrophage polarization-ferroptosis axis as a therapeutically targetable immunometabolic framework in periodontitis.

Periodontitis is a chronic inflammatory disease sustained by microbial dysbiosis, maladaptive host immunity, oxidative stress, and progressive destruction of periodontal supporting tissues. Macrophage polarization and ferroptosis have usually been discussed as separate pathological processes, but increasing evidence suggests that they may be functionally connected within the periodontal inflammatory microenvironment. This review evaluates the macrophage polarization-ferroptosis axis as an emerging and therapeutically targetable immunometabolic framework in periodontitis. We summarize how pro-inflammatory cytokine networks, iron retention, reactive oxygen species accumulation, lipid metabolic remodeling, antioxidant defense failure, ferroptosis-associated danger signaling, defective efferocytosis, and extracellular vesicle-mediated communication may contribute to the proposed crosstalk between macrophages and ferroptosis-vulnerable periodontal cells. This framework helps explain how periodontal lesions may progress from microbial-triggered inflammation to self-sustaining tissue destruction and impaired repair. Potential therapeutic opportunities include relatively higher-priority host-modulatory nodes, such as macrophage reprogramming and ferroptosis-relevant redox regulation, as well as candidate or emerging approaches, including iron modulation, biomaterial-assisted local delivery, exosome-based approaches, and adjunctive photobiomodulation. However, most current evidence remains preclinical, evidence strength varies across mechanistic nodes, cell-type specificity is incompletely resolved, and clinically validated intervention strategies are lacking. Future translation will require spatially resolved human validation, standardized macrophage and ferroptosis phenotyping, mechanism-matched target-engagement biomarkers, and locally deliverable host-modulatory platforms. Refining this framework may support mechanism-based host-modulatory strategies for periodontitis.