Epigenetic drugs in epitherapy for periodontitis: a systematic review of preclinical and clinical evidence

Epigenetic mechanisms, particularly DNA methylation and histone modifications, have emerged as key regulators of immune and inflammatory responses. By influencing gene expression without altering the underlying DNA sequence, these mechanisms play a central role in maintaining cellular homeostasis and modulating host responses to environmental stimuli. Owing to their dynamic and, in some contexts, reversible nature, epigenetic regulatory processes have gained increasing attention as potential targets for immunomodulatory therapies in chronic inflammatory diseases (Barros and Offenbacher, 2014; Meyle and Chapple, 2015). Periodontitis is a prevalent chronic inflammatory disease associated with significant morbidity and represents a paradigmatic example of a condition in which host-mediated immune responses critically shape disease onset and progression. Although genetic predisposition, environmental exposures, and lifestyle-related factors contribute to disease susceptibility, these determinants alone do not fully explain the marked inter-individual variability in disease development, severity, and progression. This observation has prompted growing interest in epigenetic regulation as an additional layer of control linking environmental cues, microbial challenge, and host inflammatory responses in periodontal pathogenesis (Loos and Van Dyke, 2020). Within this framework, epigenetic regulation represents a critical interface between genetic background, environmental and lifestyle exposures, and immune-mediated inflammation. Epigenetic modifications can be acquired throughout life in response to ageing, microbial exposure, dietary patterns, systemic conditions, and behaviors such as smoking and stress, while also exhibiting a degree of stability that may contribute intrinsically to disease susceptibility. These mechanisms influence immune fitness and inflammatory tone by modulating chromatin accessibility and transcriptional activity of genes involved in host defense and tissue homeostasis, thereby providing a biologically plausible link between external exposures and sustained inflammatory activation in periodontitis (Loos and Van Dyke, 2020). Consistent with this concept, aberrant DNA methylation profiles have been identified in periodontal tissues and peripheral samples from patients with periodontitis. Promoter-specific alterations in genes involved in inflammatory activation—including Toll-like receptor 2 (TLR2) (de Faria Amormino et al., 2013; De Oliveira et al., 2011), prostaglandin-endoperoxide synthase 2 (PTGS2) (Zhang et al., 2010a), interferon gamma gene (IFNG) (Zhang et al., 2010b), interleukin-6 (IL6) (Ishida et al., 2011; Stefani et al., 2013), interleukin-8 (IL8) (Andia et al., 2010), and tumor necrosis factor (TNF) (Asa’ad et al., 2017; Ghotloo et al., 2018; Kojima et al., 2016; Zhang et al., 2013)—have been reported in gingival tissue, peripheral blood, and buccal mucosa, often correlating with altered gene expression and clinical indicators of disease severity. In parallel, enzymes regulating histone acetylation, particularly histone deacetylases (HDACs), have been shown to exhibit dysregulated expression in periodontitis-affected gingival tissues. Experimental studies further demonstrate that infection of gingival epithelial cells, gingival fibroblasts, and periodontal ligament cells with key periodontal pathogens, such as Porphyromonas gingivalis and Treponema denticola, induces changes in the expression and activity of chromatin-modifying enzymes, accompanied by site-specific and global alterations in DNA methylation patterns and histone modification marks (Ateia et al., 2018; Grabiec and Potempa, 2018; Haas et al., 2021; Jurdziński et al., 2020; Larsson et al., 2015; Yin and Chung, 2011). The term epigenetics has been defined variably across the scientific literature. In the present review, epigenetics is considered in accordance with a widely cited unifying definition proposed by Bird (2007), namely “the structural adaptation of chromosomal regions so as to register, signal, or perpetuate altered activity states”. This definition encompasses regulatory mechanisms that may be stable over time and, in some contexts, potentially heritable, without involving alterations in the underlying DNA sequence. Within this conceptual framework, epitherapy refers to therapeutic approaches aimed at modulating epigenetic regulatory pathways. Among the epigenetic mechanisms described to date, DNA methylation and post-translational histone modifications are the most extensively characterized and have therefore been the primary focus of experimental investigations in periodontitis (Jurdziński et al., 2020). Beyond their mechanistic relevance, epigenetic alterations have also been explored as potential biomarkers in inflammatory and immune-mediated diseases. In periodontitis, candidate gene approaches and epigenome-wide association studies have identified altered DNA methylation signatures in peripheral blood and buccal epithelial cells, suggesting a possible role for epigenetic markers in disease detection or stratification (Asa’ad et al., 2017; Barros et al., 2014, 2018; Ghotloo et al., 2018; Jurdziński et al., 2020; Loos and Van Dyke, 2020; Martins et al., 2016; Meyle and Chapple, 2015). However, the interpretation of these findings is complicated by tissue-specific variability and the influence of confounding factors, including age, genetic variation, environmental exposures, microbial composition, and differences in cellular sample composition. Consequently, the relationships between epigenetic signatures and disease susceptibility, progression, or severity remain incompletely characterized and require validation in larger, well-defined cohorts. Parallel to advances in epigenetic profiling, the therapeutic targeting of epigenetic mechanisms has gained attention following the successful clinical application of epigenetic drugs in oncology and the recognition of the anti-inflammatory properties of histone deacetylase (HDAC) (Ateia et al., 2018; Cantley et al., 2016; Grabiec and Reedquist, 2010; Grabiec and Potempa, 2018; Martins et al., 2016; Yin and Chung, 2011), and bromodomain and extra-terminal (BET) protein inhibitors (Marmorstein and Zhou, 2014; Prinjha et al., 2012). Preclinical studies indicate that pharmacological modulation of these pathways may attenuate excessive inflammation, osteoclastogenesis, and alveolar bone resorption in experimental models of periodontitis. Nevertheless, translation into periodontal therapy warrants caution, given concerns regarding toxicity, cell type– and pathogen-specific effects on host defense, target selectivity, and routes of administration. These uncertainties underscore the need for a critical synthesis of the available preclinical and clinical evidence to clarify the biological impact, therapeutic potential, and current limitations of epigenetic drugs investigated within epitherapy approaches for periodontitis (Jurdziński et al., 2020; Larsson et al., 2015). Collectively, these observations support the concept that epigenetic regulation represents a key interface between genetic predisposition, environmental and lifestyle exposures, microbial challenge, and host immune responses in periodontitis. Accumulating evidence from molecular, cellular, and experimental studies indicates that epigenetic alterations—particularly those involving DNA methylation and histone modifications—are associated with dysregulated inflammatory activation, impaired tissue homeostasis, and bone remodeling in periodontal disease. At the same time, emerging data suggest that pharmacological modulation of epigenetic pathways may influence these processes, indicating that epigenetic drugs could represent host-modulatory strategies within epitherapy frameworks (Barros et al., 2018; Haas et al., 2021; Jurdziński et al., 2020; Larsson et al., 2015). However, the available evidence remains fragmented across in vitro experiments, preclinical animal models, and a limited number of clinical studies, with substantial heterogeneity in study designs, epigenetic targets, outcome measures, and levels of methodological rigor. In addition, important uncertainties persist regarding the translational relevance, safety profiles, target selectivity, and routes of administration of epigenetic drugs in the context of chronic inflammatory conditions such as periodontitis. Consequently, a comprehensive and critical synthesis of the existing preclinical and clinical evidence is required to clarify the reported biological and clinical effects of epigenetic drugs, to identify compounds with potential biotechnological relevance, and to delineate current limitations and research gaps in this evolving field.