Epigenetic memory in periodontal healing: mechanisms, evidence, and emerging therapeutic perspectives

Periodontitis is a chronic inflammatory disease characterized by progressive connective tissue and alveolar bone destruction, with recurrence frequently observed despite conventional therapy. Emerging evidence indicates that periodontal cells-including gingival fibroblasts, osteoblast progenitors, and immune cells-may acquire persistent epigenetic modifications that sustain an exaggerated inflammatory phenotype even after apparent clinical resolution. This narrative review summarizes recent evidence (2020-2025) regarding the role of epigenetic mechanisms in periodontal inflammation, wound healing, and regenerative responses, with emphasis on their biological relevance and emerging therapeutic implications. A focused narrative search of PubMed and Scopus was performed to identify representative English-language studies published between 2020 and 2025 using combinations of the terms 'periodontitis,' 'epigenetic regulation,' 'DNA methylation,' 'histone modification,' 'epigenetic memory,' and 'trained immunity.' Original experimental, molecular, translational, and selected review articles were screened based on title, abstract, and full-text relevance. Because this article was designed as a narrative review, the literature was synthesized interpretively rather than appraised systematically. Altered DNA methylation patterns in inflammatory gene promoters (e.g., IL6, TNFA) and histone modifications such as H3K27ac and H3K4me3 contribute to sustained pro-inflammatory signaling and impaired regenerative capacity. These epigenetic changes may lower the inflammatory response threshold and influence post-treatment tissue stability. Experimental evidence suggests that pharmacologic modulators (HDAC and DNMT inhibitors) and biologic agents (e.g., PRF, EMD, hyaluronic acid) may partially restore regenerative gene expression and improve cellular homeostasis. Epigenetic remodeling represents a plausible biological mechanism that may contribute to disease persistence and interindividual variability in healing outcomes. Improved understanding of epigenetic memory may help generate testable hypotheses for future host-modulation strategies and individualized periodontal care; however, current biomarker and therapeutic applications remain investigational.