Diabetes Impairs Alveolar Bone Healing via the EFHD2–STIM1–NFATC1 Axis–Mediated NK Cell Exhaustion

Objective Impaired alveolar bone regeneration following tooth extraction is a common, clinically difficult complication in patients with type 2 diabetes mellitus (T2DM). Diabetic inflammation and immune dysregulation are known to cause defective bone repair, yet the core molecular mechanisms remain unclear. This study aimed to identify the key molecular mediator connecting hyperglycemia and osteoimmunological dysfunction. Methods We combined National Health and Nutrition Examination Survey (NHANES) epidemiological cohort analysis, transcriptomic weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) regression, single-cell RNA sequencing, streptozotocin-induced diabetic rat tooth extraction animal experiments, NK-92MI cell functional detection, and molecular docking prediction. Results Glycemic markers were negatively correlated with femoral neck bone mineral density. EF-hand domain-containing protein 2 ( EFHD2 ) was identified as the hub gene shared between T2DM and bone metabolism, and its expression was significantly elevated in NK cells in a diabetic immune microenvironment. In diabetic rats, high EFHD2 expression was associated with fewer activated NKp46⁺ NK cells and impaired alveolar bone healing. High glucose upregulated EFHD2, stromal interaction molecule 1 (STIM1), and nuclear factor of activated T cells 1 (NFATC1) and downregulated NKp46 in NK-92MI cells; genistein, which which was predicted by molecular docking to have high binding affinity to EFHD2, reversed these abnormal changes. Conclusion The EFHD2–STIM1–NFATC1 signaling axis mediates hyperglycemia-triggered NK cell exhaustion and impaired alveolar bone regeneration. Genistein is a promising candidate compound targeting this axis, and EFHD2 can serve as a potential diagnostic biomarker and therapeutic target for diabetic bone complications.