Protein O-GlcNAcylation reprograms macrophage-mediated bone remodeling in medication-related osteonecrosis of the jaw

O-Linked N-acetylglucosamine (O-GlcNAcylation) is an essential nutrient-sensitive post-translational modification (PTM) that has emerged as a critical regulator bridging immunometabolic reprogramming and skeletal homeostasis. Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication of anti-resorptive therapy, with limited effective treatments available. Despite four decades of research since its discovery, the therapeutic potential of targeting O-GlcNAcylation in MRONJ remains underexplored. Macrophages orchestrate a pro-inflammatory/anti-inflammatory milieu by polarization and paracrine signaling to promote bone resorption/formation. However, during MRONJ progression, metabolic alterations reshape macrophage function, leading to immune dysregulation and impaired bone remodeling. O-GlcNAcylation serves as a metabolic sensor of nutritional status and cellular stress, influences macrophage phenotype and function, making it a potential target for therapeutic intervention. Currently, extensive research on biomaterials for bone regeneration primarily focuses on enhancing osteogenesis or inhibiting osteoclast activity, often overlooking the impact of PTMs on bone remodeling. In this review, we highlight the emerging role of O-GlcNAcylation in macrophage regulation, discuss its implications in MRONJ pathogenesis, and explore its potential applications in macrophage-targeted biomaterials and nanotherapeutics.