O-GlcNAcylation-mediated glycolytic reprogramming of CD4⁺ T cells contributes to type H vessel impairment in diabetic osteoporosis

Diabetic osteoporosis (DOP) is a metabolic bone disease characterized by skeletal fragility and impaired angiogenesis-osteogenesis coupling, in which type H vessel impairment has emerged as an important pathological feature. While adaptive immunity is known to regulate bone homeostasis, the immunometabolic mechanisms driving vascular dysfunction in DOP remain elusive. Here, we investigated whether pathological metabolic reprogramming of CD4⁺ T cells is linked to type H vessel impairment in DOP. CD4⁺ T cells from DOP mice exhibited enhanced glycolytic activation accompanied by increased hexokinase 2 (HK2) expression and elevated O-GlcNAcylation. In vitro, high glucose and palmitic acid (HGPA) treatment was associated with increased HK2 O-GlcNAcylation, HK2 stabilization, mitochondrial localization, and enhanced glycolytic activity in CD4⁺ T cells. These metabolic alterations were accompanied by senescence-associated and pro-inflammatory phenotypes, including upregulation of P53, P16, PD-1, IL-6, and IL-17A, as well as enhanced T helper 17 (Th17) polarization. Co-culture experiments showed that HGPA-treated CD4⁺ T cells were associated with impaired endothelial viability, migration, tube formation, and reduced VEGFA/VEGFR2 expression. Pharmacological inhibition of O-GlcNAcylation or glycolysis partially attenuated CD4⁺ T cell dysfunction and improved endothelial angiogenic function. Collectively, these findings suggest that O-GlcNAcylation-associated HK2 glycolytic activation may contribute to CD4⁺ T cell dysfunction and type H vessel impairment in DOP. Targeting this immunometabolic pathway may represent a potential therapeutic strategy for diabetic skeletal complications.