Dai Linrui, Rui Shunli, Yang Mengling, Yu Shiyan, Chen Qingqing, Wang Hongyan, Deng Bo, Deng Liling, Hao Wei, Wu Xiaohua, Armstrong David G, Cao Zhidong, Duan Xiaodong, Deng Wuquan
Department of Endocrinology and Metabolism, School of Medicine, Chongqing University Central Hospital, Chongqing Emergency Medical Centre, Chongqing University, Chongqing, 400014, China.
Chongqing Key Laboratory of Emergency Medicine, Chongqing Emergency Medical Center, School of Medicine, Chongqing University Central Hospital, Chongqing University, Chongqing, 400014, China.
Eur J Med Res. 2025 Aug 13;30(1):748. doi: 10.1186/s40001-025-03012-5.
BACKGROUND: Diabetic foot ulcer (DFU) is characterized by impaired wound healing and chronic inflammation, partly driven by the excessive formation of neutrophil extracellular traps (NETs). However, the molecular mediators linking NETs to failed tissue regeneration remain poorly understood. This study aimed to identify and validate novel NETs-associated biomarkers in DFU using an integrative bioinformatics and machine learning approach. METHODS: Differentially expressed genes (DEGs) were identified from the GEO dataset GSE134431. These DEGs were intersected with a NETs-related gene set to identify NETs-associated DEGs (NETDEGs). LASSO logistic regression and Random Forest algorithms were applied to the NETDEGs to select key feature genes. The top candidate, Fibroblast Growth Factor Receptor 2 (FGFR2), was validated in two independent datasets (GSE7014 and GSE147890). Its expression was further confirmed in human DFU tissues and diabetic mouse models using qPCR and immunohistochemistry. The effect of a high-glucose environment on FGFR2 expression in neutrophils was assessed in vitro. Finally, molecular docking technique was used to screen for existing drugs targeting FGFR2, with top candidates validated at the cellular level. RESULTS: Our analysis identified FGFR2 as a key downregulated gene at the intersection of DFU pathology and NETs-related pathways. FGFR2 expression was significantly reduced in DFU tissues across all datasets and in our experimental models, where its downregulation correlated with increased NETs accumulation. FGFR2 demonstrated strong diagnostic potential, with an AUC of 1.00 in the training set. In vitro, high glucose conditions suppressed FGFR2 expression in neutrophils. From 32 glucose-lowering drugs, Canagliflozin and Gliquidone were found to significantly upregulate FGFR2 protein expression in neutrophils, suggesting a potential modulatory effect. CONCLUSIONS: FGFR2 is a promising potential biomarker associated with NET-driven inflammation in DFU. Its downregulation in the diabetic wound microenvironment and its modulation by existing pharmacological agents suggest that targeting the FGFR2 pathway may be a viable future therapeutic strategy for improving DFU healing outcomes. Further preclinical validation is warranted.
背景：糖尿病足溃疡（DFU）的特征是伤口愈合受损和慢性炎症，部分原因是中性粒细胞胞外陷阱（NETs）过度形成。然而，将NETs与组织再生失败联系起来的分子介质仍知之甚少。本研究旨在使用综合生物信息学和机器学习方法，识别和验证DFU中与NETs相关的新型生物标志物。 方法：从GEO数据集GSE134431中鉴定差异表达基因（DEGs）。将这些DEGs与NETs相关基因集进行交叉分析，以识别与NETs相关的DEGs（NETDEGs）。应用LASSO逻辑回归和随机森林算法对NETDEGs进行分析，以选择关键特征基因。排名第一的候选基因成纤维细胞生长因子受体2（FGFR2）在两个独立数据集（GSE7014和GSE147890）中得到验证。使用qPCR和免疫组织化学在人DFU组织和糖尿病小鼠模型中进一步证实其表达。在体外评估高糖环境对中性粒细胞中FGFR2表达的影响。最后，使用分子对接技术筛选靶向FGFR2的现有药物，并在细胞水平上验证排名靠前的候选药物。 结果：我们的分析确定FGFR2是DFU病理学与NETs相关途径交叉点处一个关键的下调基因。在所有数据集中的DFU组织以及我们的实验模型中，FGFR2表达均显著降低，其下调与NETs积累增加相关。FGFR2具有很强的诊断潜力，在训练集中的AUC为1.00。在体外，高糖条件抑制中性粒细胞中FGFR2的表达。在32种降糖药物中，发现卡格列净和格列喹酮可显著上调中性粒细胞中FGFR2蛋白表达，提示其具有潜在调节作用。 结论：FGFR2是一种有前景的潜在生物标志物，与DFU中NET驱动的炎症相关。其在糖尿病伤口微环境中的下调以及现有药物对其的调节作用表明，靶向FGFR2途径可能是未来改善DFU愈合结果的可行治疗策略。需要进一步的临床前验证。
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