Elimination of a neutrophil Pad4 byproduct restores stem cell-mediated bone regeneration in hyperglycemia

Hyperglycemia impairs stem cell-mediated bone regeneration, yet the responsible immunometabolic block remains undefined. We identify a neutrophil-Pad4-metabolite axis that suppresses osteogenesis. In rat models of chronic and intermittent hyperglycemia, neutrophils activate ERK/JNK-AP‑1, upregulate Pad4, and generate 4‑guanidinobutyric acid (4‑GBA). 4‑GBA binds alkaline phosphatase (ALP) on jawbone mesenchymal stem cells (JBMSCs), inhibits ALP, and reduces mineralization. Padi4 deletion accelerates socket healing under hyperglycemia. To restore osteogenesis, we engineer GBASpongel, a peptide hydrogel that captures 4‑GBA at the defect. Local GBASpongel treatment rescues ALP activity, osteogenic gene expression, and bone formation in hyperglycemic rats, and improves jawbone regeneration in hyperglycemic rabbits and beagle dogs. Binding assays show micromolar affinity between 4‑GBA and ALP. Transcriptomic and metabolomic analyses corroborate pathway activation and rescue. Neutrophil-derived 4-GBA directly links hyperglycemia to impaired JBMSC function, and locally targeting this metabolite provides a translational approach to restore bone healing in dysglycemia.