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.