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<p>Diabetic periodontitis (DPD) is a severe inflammatory complication characterized by accelerated destruction of periodontal tissues and dysregulated immune responses. Gingival fibroblast (GF)-macrophage interactions drive DPD progression, but the mechanisms linking hyperglycemia, mitochondrial dysfunction, and immune activation remain unclear. Single-cell sequencing analysis of diabetic gingival tissues revealed significant apoptotic activation of GFs, closely linked to mitochondrial dysregulation. Inflammation and metabolic stress disrupt mitochondrial quality-control pathways and promote the overproduction of reactive oxygen species, inducing defective mitophagy. Crucially, apoptotic GFs secrete thrombospondin-1 (THBS-1), which binds to the CD36 receptor on the surface of macrophages, triggering NF-κB-mediated M1 polarization and pro-inflammatory cytokine production. Molecular modelling demonstrated a high-affinity interaction between THBS-1 and CD36. Gene silencing of THBS-1 in GFs or CD36 in macrophages effectively inhibited these changes, confirming the specificity of this cellular crosstalk mechanism. These findings together indicate mediation of hyperglycemia-induced mitochondrial dysfunction through the promotion of GF apoptosis and subsequent THBS-1/CD36/NF-κB-signaling-dependent macrophage activation. Thus, enhanced mitophagy and modulation of the THBS-1/CD36 axis are promising therapeutic strategies to break the self-perpetuating cycle of inflammation and tissue destruction in DPD.</p>

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Impaired Mitophagy-Induced Apoptosis of Gingival Fibroblasts Exacerbates Diabetic Periodontitis Via THBS-1/CD36-Dependent Macrophage Activation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月14日

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  • Rundong Yuan,
  • Lingxiao Meng,
  • Minglei Zhang,
  • Hongrui Liu,
  • Jie Guo,
  • Minqi Li

摘要

Diabetic periodontitis (DPD) is a severe inflammatory complication characterized by accelerated destruction of periodontal tissues and dysregulated immune responses. Gingival fibroblast (GF)-macrophage interactions drive DPD progression, but the mechanisms linking hyperglycemia, mitochondrial dysfunction, and immune activation remain unclear. Single-cell sequencing analysis of diabetic gingival tissues revealed significant apoptotic activation of GFs, closely linked to mitochondrial dysregulation. Inflammation and metabolic stress disrupt mitochondrial quality-control pathways and promote the overproduction of reactive oxygen species, inducing defective mitophagy. Crucially, apoptotic GFs secrete thrombospondin-1 (THBS-1), which binds to the CD36 receptor on the surface of macrophages, triggering NF-κB-mediated M1 polarization and pro-inflammatory cytokine production. Molecular modelling demonstrated a high-affinity interaction between THBS-1 and CD36. Gene silencing of THBS-1 in GFs or CD36 in macrophages effectively inhibited these changes, confirming the specificity of this cellular crosstalk mechanism. These findings together indicate mediation of hyperglycemia-induced mitochondrial dysfunction through the promotion of GF apoptosis and subsequent THBS-1/CD36/NF-κB-signaling-dependent macrophage activation. Thus, enhanced mitophagy and modulation of the THBS-1/CD36 axis are promising therapeutic strategies to break the self-perpetuating cycle of inflammation and tissue destruction in DPD.