Epigenetic dysregulation in osteonecrosis of the femoral head: a critical review of DNA methylation, histone modifications, and clinical translation

Osteonecrosis of the Femoral Head (ONFH) is a progressive osteoarticular disease caused by local ischemia, ultimately leading to femoral head collapse and loss of joint function. Epigenetics has emerged as a pivotal tool for unraveling the complex pathogenesis of ONFH, with DNA methylation and histone modifications playing central roles. These key epigenetic mechanisms critically regulate osteocyte function, bone remodeling, and angiogenesis. Aberrant DNA methylation silences osteogenic genes, e.g., runt-related transcription factor 2(RUNX2), bone morphogenetic protein 2(BMP2) and angiogenic factors (e.g., VEGF), thereby impairing bone repair and revascularization. Concurrently, histone modifications (e.g., H3K27ac, H3K27me3) dynamically modulate chromatin accessibility, influencing osteocyte fate and bone remodeling homeostasis. These epigenetic alterations interact with signaling pathways such as Wnt/β-catenin, PI3K/Akt, and HIF-1α, forming a regulatory network that drives disease progression. However, the precise molecular mechanisms and interactive networks remain incompletely elucidated. This review systematically summarizes recent advances regarding the roles of DNA methylation and histone modifications in ONFH, discusses their impact on disease pathology, and aims to provide a theoretical foundation and identify potential targets for early diagnosis and precision therapy of ONFH.