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<p>In diabetic skin, even in the absence of infection, the antiviral enzymes 2′-5′-oligoadenylate synthetase (OAS) and ribonuclease L (RNase L) demonstrate abnormally heightened activity. This dysregulation triggers a state of cellular stress, which not only suppresses intracellular protein synthesis but also activates innate immune responses—particularly upon pathogenic bacterial invasion. Whether the sustained activation of the OAS–RNase L pathway in diabetic skin tissue critically contributes to impaired wound healing remains to be determined. We have investigated the pyroptosis changes in human umbilical vein endothelial cells (HUVECs) treated with Lipopolysaccharide (LPS) under high glucose by RNase L small interfering RNA (siRNA) to down-regulate RNase L expression. Under high glucose conditions, we observed abnormal activation of the OAS/RNase L pathway in HUVECs, which further exacerbated cellular pyroptosis upon LPS stimulation. Abnormally activated RNase L, which reduces the expression of methyltransferase 3 (METTL3), led to decreased m<sup>6</sup>A methylation of thioredoxin-interacting protein mRNA (TXNIP mRNA). The decreased degradation of TXNIP mRNA by the hypomethylation leads to increased TXNIP expression, which in turn enhances pyroptosis.. In vitro experiments, the impact of RNase L inhibitor Ellagic acid (EA) on diabetic wound healing in STZ (streptozotocin)-induced diabetic mice was evaluated. We found a reduction in skin pyroptosis and improved wound healing when <i>EA</i> was administered orally. Our results demonstrate that hyperglycemia-induced OAS/RNase L activation increases endothelial cell susceptibility to pyroptosis and inflammatory responses during infection. These findings provide valuable insights for developing novel therapeutic strategies for diabetic wound management.</p>

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Activated oligoadenylate synthetase-ribonuclease L pathway promotes endothelial pyroptosis and impairs diabetic wound healing via thioredoxin-interacting protein m6A methylation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月29日

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  • Peng Zhou,
  • Yating Huang,
  • Zezheng Wang,
  • Dianxi Chen,
  • Binbin Long,
  • Peiliang Qin,
  • Yiqing Li,
  • Chao Yang,
  • Qin Li

摘要

In diabetic skin, even in the absence of infection, the antiviral enzymes 2′-5′-oligoadenylate synthetase (OAS) and ribonuclease L (RNase L) demonstrate abnormally heightened activity. This dysregulation triggers a state of cellular stress, which not only suppresses intracellular protein synthesis but also activates innate immune responses—particularly upon pathogenic bacterial invasion. Whether the sustained activation of the OAS–RNase L pathway in diabetic skin tissue critically contributes to impaired wound healing remains to be determined. We have investigated the pyroptosis changes in human umbilical vein endothelial cells (HUVECs) treated with Lipopolysaccharide (LPS) under high glucose by RNase L small interfering RNA (siRNA) to down-regulate RNase L expression. Under high glucose conditions, we observed abnormal activation of the OAS/RNase L pathway in HUVECs, which further exacerbated cellular pyroptosis upon LPS stimulation. Abnormally activated RNase L, which reduces the expression of methyltransferase 3 (METTL3), led to decreased m6A methylation of thioredoxin-interacting protein mRNA (TXNIP mRNA). The decreased degradation of TXNIP mRNA by the hypomethylation leads to increased TXNIP expression, which in turn enhances pyroptosis.. In vitro experiments, the impact of RNase L inhibitor Ellagic acid (EA) on diabetic wound healing in STZ (streptozotocin)-induced diabetic mice was evaluated. We found a reduction in skin pyroptosis and improved wound healing when EA was administered orally. Our results demonstrate that hyperglycemia-induced OAS/RNase L activation increases endothelial cell susceptibility to pyroptosis and inflammatory responses during infection. These findings provide valuable insights for developing novel therapeutic strategies for diabetic wound management.