The role of post-translational modifications in osteonecrosis of the femoral head

Background Osteonecrosis of the femoral head (ONFH) is a progressive and disabling orthopedic disorder characterized by impaired bone remodeling and microvascular dysfunction. Emerging evidence identifies post-translational modifications (PTMs) as critical molecular switches linking external pathogenic stimuli, such as glucocorticoids and alcohol, to intracellular signaling dysregulation in ONFH. Main Body This review comprehensively summarizes the regulatory roles of major PTMs-including phosphorylation, acetylation, methylation, and ubiquitination-in key cell types governing femoral head homeostasis, namely, bone marrow-derived mesenchymal stem cells, osteoblasts, osteocytes, osteoclasts, and vascular endothelial cells. Aberrant PTMs disrupt the osteogenic-adipogenic balance, impair angiogenesis, and trigger multiple forms of programmed cell death, including apoptosis and ferroptosis, collectively driving the pathological progression towards bone necrosis. Particular emphasis is placed on phosphorylation-dependent signaling pathways (e.g., PI3K/Akt, GSK-3β/β -catenin, JAK2/STAT3, and AMPK/mTOR), ubiquitin-mediated mitochondrial quality control, and acetylation-driven epigenetic regulation. Furthermore, we highlight emerging PTM-targeted small-molecule interventions that show promise in restoring osteogenesis, preserving endothelial function, or suppressing cell death. Conclusion Future research directions include decoding cell type-specific “PTM codes”, integrating multi-omics analyses, and developing patient-derived organoid models. Advancing these areas may collectively enable earlier diagnosis and more precise, mechanism-based therapies for ONFH.