Osteoarthritis (OA) is a common chronic degenerative joint disease characterized by progressive cartilage destruction, synovial inflammation, subchondral bone remodeling, and functional decline. Current treatments remain largely symptomatic and are unable to effectively halt or reverse disease progression. Increasing evidence indicates that epigenetic regulation provides a critical link between genetic susceptibility, mechanical loading, inflammation, aging, metabolic abnormalities, and pathological gene expression in OA. This review summarizes recent advances in OA epigenetics, with a particular focus on studies published over the past 2 years. We discuss classical mechanisms, including DNA methylation, histone modifications, and non-coding RNA-mediated regulation, and further highlight emerging epigenomic layers such as chromatin accessibility, enhancer and super-enhancer remodeling, three-dimensional genome organization, tissue-specific regulation, and the integration of genetics with single-cell and spatial multi-omics. These mechanisms contribute to inflammatory activation, chondrocyte metabolic imbalance, extracellular matrix degradation, programmed cell death, cellular senescence, oxidative stress, and abnormal inter-tissue crosstalk. Epigenetic biomarkers and epigenetic-based interventions, including extracellular vesicle-mediated delivery, engineered RNA therapeutics, and small-molecule epigenetic drugs, may offer new opportunities for early diagnosis, disease stratification, and precision therapy. However, current studies are limited by model heterogeneity, sample variability, insufficient causal validation, limited reproducibility, and translational challenges related to delivery and safety. Overall, epigenetic regulation provides a systematic framework for understanding OA heterogeneity and progression and may promote the development of disease-modifying therapeutic strategies.
