Hexokinase HK2 Activates STING Pathway to Exacerbate Bone Resorption in Apical Periodontitis

doi:10.13701/j.cnki.kqyxyj.2025.06.004

Abstract

Abstract: Objective: To investigate the molecular mechanism by which hexokinase 2 (HK2) regulates bone resorption in apical periodontitis. Methods: Using RNA sequencing, the differences in glycolysis gene expression between human apical cysts/granulomas and normal mucosa were analyzed. Protein expression of HK2 was detected by immunohistochemistry. In vitro experiments: bone marrow-derived macrophages (BMDMs) were treated with lipopolysaccharides (LPS) and HK2 inhibitor 2-deoxy-D-glucose (2DG). Activation of the stimulator of interferon genes (STING) pathway was analyzed by Western blot, and osteoclast differentiation ability was assessed by tartrate resistant acid phosphatase (TRAP) staining. In vivo experiments: C57/BL6 mice were intraperitoneally injected with 2DG while establishing a periapical periodontitis model (14 days/28 days). Bone resorption was quantified by micro-CT, osteoclasts were counted by TRAP staining in apical periodontitis tissue sections, and the expressions of HK2 and STING were detected by immunohistochemistry. Results: Glycolysis-related genes were significantly up-regulated in apical periodontitis tissues. Immunohistochemical results showed that the expression of HK2 was significantly increased. After inhibition of HK2 by 2DG, the expression level of STING in LPS-induced BMDMs was decreased by 23.6% (P＜0.05), and osteoclast differentiation induced by LPS in BMDMs was reduced by 22.2% (P＜0.01). Animal experiments showed that 2DG treatment reduced the bone resorption, osteoclast number, and STING expression in mice with apical periodontitis. Conclusion: HK2-mediated glycolysis promotes macrophage osteoclastic differentiation by activating the STING signaling pathway. Inhibition of HK2 can alleviate bone resorption in apical periodontitis.

Key words: apical periodontitis, glycolysis, HK2, STING, alveolar bone resorption

LI Jiaqi, CHENG Shi, ZHOU Lu, WEN Yuanhao, MAO Hanqing, ZHANG Lu. Hexokinase HK2 Activates STING Pathway to Exacerbate Bone Resorption in Apical Periodontitis[J]. Journal of Oral Science Research, 2025, 41(6): 469-476.

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