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<p>Diabetic retinopathy (DR) and diabetic nephropathy (DN) are major microvascular complications whose progression is often sustained despite glycemic normalization, consistent with metabolic memory. Accumulating evidence indicates that histone modification dysregulation provides a mechanistic substrate for this persistence. Across both DR and DN, three conserved nodes emerge: activating H3K4 methylation programs driven by SET7/9, inflammatory chromatin opening promoted by H3K27me3 erasure via KDM6A, and early loss of the protective SIRT1/SIRT6 deacetylation axis. In parallel, metabolite-sensitive marks such as histone lactylation offer an additional route by which metabolic perturbations are written into the epigenome. Importantly, these shared mechanisms are executed in tissue-specific cellular units, producing divergent outcomes within the retinal neurovascular unit versus renal filtration and tubular compartments. Finally, we outline translational opportunities and propose an epigenetic precision-medicine framework in which stage- and cell-specific combinatorial signatures support biomarker development, patient stratification, and targeted intervention, while highlighting key gaps including the long-term and potentially intergenerational consequences of epigenetic memory.</p>

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Beyond hyperglycemia: histone modification-mediated epigenetic dysregulation in diabetic retinopathy and nephropathy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月20日

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  • Minxuan Tang,
  • Hongyu Zhu,
  • Suyan Li,
  • Lei Qiao

摘要

Diabetic retinopathy (DR) and diabetic nephropathy (DN) are major microvascular complications whose progression is often sustained despite glycemic normalization, consistent with metabolic memory. Accumulating evidence indicates that histone modification dysregulation provides a mechanistic substrate for this persistence. Across both DR and DN, three conserved nodes emerge: activating H3K4 methylation programs driven by SET7/9, inflammatory chromatin opening promoted by H3K27me3 erasure via KDM6A, and early loss of the protective SIRT1/SIRT6 deacetylation axis. In parallel, metabolite-sensitive marks such as histone lactylation offer an additional route by which metabolic perturbations are written into the epigenome. Importantly, these shared mechanisms are executed in tissue-specific cellular units, producing divergent outcomes within the retinal neurovascular unit versus renal filtration and tubular compartments. Finally, we outline translational opportunities and propose an epigenetic precision-medicine framework in which stage- and cell-specific combinatorial signatures support biomarker development, patient stratification, and targeted intervention, while highlighting key gaps including the long-term and potentially intergenerational consequences of epigenetic memory.