Han Ziyang, Wu Weiping, Bai Zeming, Xiu Yiping, Zhou Dapeng
Burn and Plastic Surgery Department, General Hospital of Northern Theater Command, Shenyang, China.
Front Pharmacol. 2025 Apr 30;16:1578625. doi: 10.3389/fphar.2025.1578625. eCollection 2025.
Diabetic wounds are a severe complication of diabetes, with persistently high incidence and mortality rates, often leading to severe clinical outcomes such as amputation. Beta-boswellic acid (β-BA) is a plant-derived pentacyclic triterpene with activities of inflammatory control and ferroptosis regulation. However, the protective effect of β-BA on DW has not been described.
We employed network analysis approaches and molecular docking to predict the potential targets and pathways of β-BA in the treatment of diabetic wounds (DW). Both and models were established, including high-glucose-induced fibroblast models and diabetic rat wound models. The effects of β-BA on diabetic wounds were investigated through CCK-8 assay, wound healing assay, immunofluorescence staining, western blotting, fluorescent probe analysis, gross observation, and histopathological experiments.
In this study, we predicted potential targets for β-BA using public databases and identified 29 key genes, with STAT3 being the most significant. GO analysis revealed that these targets are involved in biological processes closely related to ferroptosis, such as regulation of inflammatory response and lipid metabolism. Our results showed that HG induced ferroptosis in HSFs, as evidenced by decreased cell viability, altered GSH/MDA, Fe2+, and ROS levels, and changes in the expression of ferroptosis-related genes ACSL4 and GPX4. Notably, treatment with the ferroptosis inhibitor Ferr-1 partly reversed these effects. CCK-8 assays showed that β-BA improved HSFs viability in a concentration-dependent manner. Immunofluoresc-ence staining and further biochemical analyses demonstrated that β-BA reduced Fe2+ and lipid peroxide levels, prevented oxidative damage, and improved cell migration ability impaired by HG. Western blot analysis confirmed that β-BA reversed the changes in ACSL4 and GPX4 expression induced by HG. Molecular docking validated the potential binding between β-BA and STAT3. Western blot analysis revealed that β-BA increased the level of phosphorylated STAT3 in HSFs. Introducing a STAT3 inhibitor diminished the beneficial effects of β-BA on HG-induced cell dysfunction and suppressed its protective effect against ferroptosis. Finally, we assessed the efficacy of β-BA in the treatment of diabetic wounds in rats. BA administration accelerated wound closure, reduced inflammatory cell infiltration, improved granulation tissue arrangement, and increased collagen deposition. Immunohistochemical staining showed that BA upregulated the number of STAT3-positive cells and upregulated the number of GPX4-positive cells in the wounds, suggesting that BA can inhibit ferroptosis and accelerate wound healing in diabetic rats.
Our findings suggested that β-BA may exert its therapeutic effects on diabetic wounds by targeting STAT3 and inhibiting ferroptosis.
糖尿病伤口是糖尿病的一种严重并发症，发病率和死亡率持续居高不下，常导致截肢等严重临床后果。β-乳香酸（β-BA）是一种植物来源的五环三萜，具有炎症控制和铁死亡调节活性。然而，β-BA对糖尿病伤口的保护作用尚未见报道。
我们采用网络分析方法和分子对接来预测β-BA治疗糖尿病伤口（DW）的潜在靶点和途径。建立了体外和体内模型，包括高糖诱导的成纤维细胞模型和糖尿病大鼠伤口模型。通过CCK-8检测、伤口愈合检测、免疫荧光染色、蛋白质印迹、荧光探针分析、大体观察和组织病理学实验研究了β-BA对糖尿病伤口的影响。
在本研究中，我们利用公共数据库预测了β-BA的潜在靶点，鉴定出29个关键基因，其中信号转导和转录激活因子3（STAT3）最为显著。基因本体（GO）分析表明，这些靶点参与了与铁死亡密切相关的生物学过程，如炎症反应调节和脂质代谢。我们的结果表明，高糖诱导人皮肤成纤维细胞（HSFs）发生铁死亡，表现为细胞活力下降、谷胱甘肽/丙二醛（GSH/MDA）、铁离子（Fe2+）和活性氧（ROS）水平改变，以及铁死亡相关基因长链脂酰辅酶A合成酶4（ACSL4）和谷胱甘肽过氧化物酶4（GPX4）表达变化。值得注意的是，铁死亡抑制剂Fer-1处理部分逆转了这些效应。CCK-8检测表明，β-BA以浓度依赖的方式提高HSFs活力。免疫荧光染色和进一步的生化分析表明，β-BA降低了Fe2+和脂质过氧化物水平，防止了氧化损伤，并改善了高糖损伤的细胞迁移能力。蛋白质印迹分析证实，β-BA逆转了高糖诱导的ACSL4和GPX4表达变化。分子对接验证了β-BA与STAT3之间的潜在结合。蛋白质印迹分析显示，β-BA增加了HSFs中磷酸化STAT3的水平。引入STAT3抑制剂可减弱β-BA对高糖诱导的细胞功能障碍的有益作用，并抑制其对铁死亡的保护作用。最后，我们评估了β-BA治疗大鼠糖尿病伤口的疗效。给予β-BA可加速伤口闭合，减少炎症细胞浸润，改善肉芽组织排列，并增加胶原蛋白沉积。免疫组织化学染色显示，β-BA上调了伤口中STAT3阳性细胞的数量和GPX4阳性细胞的数量，表明β-BA可抑制铁死亡并加速糖尿病大鼠伤口愈合。
我们的研究结果表明，β-BA可能通过靶向STAT3并抑制铁死亡对糖尿病伤口发挥治疗作用。
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