Impaired wound healing is a major complication of diabetes and involves sustained inflammation and oxidative stress at the wound site. Here, we investigated the potential involvement of ferroptosis, a newly discovered form of cell death characterized by iron-dependent accumulation of lipid peroxides, in the pathogenesis of diabetic wound healing. Fibroblasts and vascular endothelial cells exposed to high glucose concentrations in vitro contained elevated levels of reactive oxygen species (ROS), lipid peroxidation products, and ferroptosis-associated proteins, and displayed reduced survival and migration. These effects of high glucose were all significantly reduced by treatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1). Similarly, in a rat model of diabetes, direct application of Fer-1 to the wound site reduced the expression of oxidative stress and inflammation markers and accelerated wound healing via activation of the anti-inflammatory phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. Our results implicate ferroptosis in wound healing and identify a potential new therapeutic target for difficult-to-treat diabetic wounds.

中文翻译：

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糖尿病铁死亡在引发糖尿病伤口炎症中起重要作用

伤口愈合受损是糖尿病的主要并发症，涉及伤口部位的持续炎症和氧化应激。在这里，我们研究了铁死亡（一种新发现的细胞死亡形式，其特征是脂质过氧化物的铁依赖性积累）在糖尿病伤口愈合的发病机制中的潜在参与。体外暴露于高葡萄糖浓度的成纤维细胞和血管内皮细胞含有升高水平的活性氧 (ROS)、脂质过氧化产物和铁死亡相关蛋白，并显示存活和迁移降低。用铁死亡抑制剂 ferrostatin-1 (Fer-1) 处理后，高血糖的这些影响都显着降低。同样，在糖尿病大鼠模型中，Fer-1 直接应用于伤口部位可降低氧化应激和炎症标志物的表达，并通过激活抗炎磷酸肌醇 3-激酶 (PI3K)/蛋白激酶 B (AKT) 途径加速伤口愈合。我们的结果表明伤口愈合中铁死亡，并为难以治疗的糖尿病伤口确定了一个潜在的新治疗靶点。