Ferroptosis in Periodontal Disease: Molecular Mechanisms, Biomarkers, and Emerging Therapeutic Strategies

Abstract

Periodontitis is a chronic, microbially initiated inflammatory disease that destroys the tooth-supporting apparatus and remains one of the most prevalent non-communicable conditions worldwide. Despite advances in mechanical and antimicrobial therapy, disease recurrence and progressive attachment loss persist in a substantial proportion of patients, indicating that host-derived pathways beyond microbial burden sustain tissue destruction. Ferroptosis, an iron-dependent, lipid peroxidation-driven form of regulated cell death mechanistically distinct from apoptosis, necroptosis and pyroptosis, has recently emerged as one such pathway. Iron accumulation, depletion of the glutathione pool, inactivation of glutathione peroxidase 4 and accumulation of polyunsaturated phospholipid peroxides have each been documented in gingival, periodontal ligament, epithelial, osteogenic and immune cell populations exposed to periodontal pathogens and their metabolites. This review synthesises the current understanding of ferroptotic mechanisms operating within the periodontal microenvironment, integrating evidence on microbial and metabolic triggers, cell-type-specific vulnerability, candidate salivary and gingival crevicular fluid biomarkers, and pharmacological strategies capable of modulating this pathway, including ferrostatin-type inhibitors, iron chelators, nuclear factor erythroid 2-related factor 2 activators and selected phytochemicals. The relationship between ferroptosis and diabetes-associated periodontal destruction is also considered, given the shared dependence of both conditions on redox imbalance and iron dyshomeostasis. Across periodontal cell types, ferroptosis appears to behave as a double-edged process: clearly pathogenic when it depletes structural and regenerative cell populations such as fibroblasts, periodontal ligament cells and osteoblasts, though its role within osteoclasts and other resorptive or immune populations remains considerably less well defined. This asymmetry complicates the translation of ferroptosis-targeted interventions into clinical practice and underscores the need for cell-selective delivery approaches. The review concludes by outlining priority research directions, summarising the state of the evidence, and identifying the principal limitations of the current literature, most notably its reliance on preclinical models and the scarcity of longitudinal human data linking ferroptotic biomarkers to clinical periodontal outcomes.