Epigenetic Regulation of Inflammation in Osteoarthritis: Mechanisms, Network Crosstalk, and Therapeutic Implications

Osteoarthritis (OA) is a degenerative disease of the whole joint characterized by progressive cartilage loss, osteophyte formation, subchondral bone remodeling, synovitis, infrapatellar fat pad dysfunction, pain, and functional disability. Although OA is not traditionally classified as an autoimmune arthritis, accumulating evidence indicates that low-grade, persistent inflammation plays a pivotal role in disease initiation, structural progression, pain sensitization, and resistance to therapy. Epigenetic mechanisms, including RNA modifications, DNA methylation and demethylation, histone modifications, and noncoding RNAs, represent a plausible form of molecular memory through which mechanical overload, metabolic stress, aging, and inflammatory exposure are translated into sustained gene expression programs. In this narrative review, we summarize the contribution of epigenetic regulation to inflammatory networks in OA involving chondrocytes, synoviocytes, macrophages, subchondral bone cells, infrapatellar fat pad-derived cells, and pain-related neuroimmune pathways. We further examine the crosstalk among inflammation, autophagy, ferroptosis, pyroptosis, glycolysis, and nociceptive sensitization while distinguishing direct epigenetic mechanisms from broader ubiquitin-dependent inflammatory signaling pathways. Finally, we critically evaluate current therapeutic strategies based on evidence strength, molecular specificity, administration route, and translational risk. The available evidence supports epigenetic regulation as a convergent mechanism underlying OA inflammation; however, most existing studies remain preclinical, tissue-specific, and model-dependent. Future research should integrate multiomics approaches, spatial tissue mapping, validated mechanical and multicellular models, pain-related endpoints, and clinically relevant delivery systems to facilitate the translation of epigenetic insights into effective disease-modifying therapies for OA.