Liu Tingting, Pan Tingting, Chang Mingxin, Fu Shaojie, Xu Hongzhao, Wu Hao, Xu Zhonggao, Cheng Yanli
Department of Nephrology, The First Hospital of Jilin University, Changchun, China.
Department of Anaesthesiology, The First Hospital of Jilin University, Changchun, China.
Front Med (Lausanne). 2025 Aug 7;12:1612200. doi: 10.3389/fmed.2025.1612200. eCollection 2025.
Immunoglobulin A nephropathy (IgAN), recognized as the leading cause of primary glomerular disease worldwide, continues to present unresolved complexities in its underlying pathogenic mechanisms. Emerging evidence underscores ferroptosis, an iron-mediated regulated cell death pathway driven by the accumulation of lipid peroxides, as a potential contributor to various pathological conditions. Despite growing interest in this field, the exact molecular pathways governing ferroptosis activation in IgAN progression remain incompletely understood and require systematic investigation. The aim of this study was to identify ferroptosis-related feature gene (FFG) for the potential diagnosis of IgAN and to investigate its relationship with renal immune cell infiltration.
Renal tissue microarray datasets (GSE93798, GSE104948, GSE99339) from IgAN patients and normal controls were retrieved from GEO database. The ferroptosis-related genes were obtained from the Ferrb database. Machine learning algorithms (LASSO, SVM-RFE, random forest) were employed to screen FFGs. The findings were validated in an IgAN mouse model using immunohistochemistry and western blotting. Gene set enrichment analysis (GSEA) was conducted to explore the underlying mechanism of FFG in IgAN. Immune cell infiltration characteristics were also analyzed vis CIBERSORT algorithm.
A total of 180 ferroptosis-related differentially expressed genes were identified in IgAN. Among them, dual specificity phosphatase 1 (DUSP1) was screened as FFG by three machine learning algorithms. DUSP1 exhibited significant downregulation in renal tissues of both IgAN patients and mice. Enhanced transcriptional abundance demonstrated significant positive associations with ferroptosis-associated biomarkers glutathione peroxidase-4 (GPX4) and cystine/glutamate antiporter (SLC7A11/xCT), while displaying an inverse relationship with acyl-CoA synthetase long-chain isoform 4 (ACSL4) expression. GSEA further identified DUSP1's functional enrichment in critical signaling networks, particularly mitogen-activated protein kinase (MAPK) cascades, ERBB receptor tyrosine kinase pathways, and Janus kinase-signal transducer (JAK-STAT) transduction mechanisms. Immunoinfiltration analysis demonstrated increased infiltration of T follicular helper cells, activated NK cells, and M1 macrophages in the renal tissues of IgAN patients, with DUSP1 expression showing negative correlations with these proinflammatory cell types.
Our research successfully identified DUSP1 as a ferroptosis-related biomarker in IgAN patients, and explored its potential mechanism in the pathogenesis of IgAN and its potential relationship with immune cell infiltration. These findings are of great significance for the diagnosis and prospective treatment strategies for IgAN patients.
免疫球蛋白A肾病（IgAN）是全球原发性肾小球疾病的主要病因，其潜在致病机制仍存在未解决的复杂性。新出现的证据强调，铁死亡是一种由脂质过氧化物积累驱动的铁介导的调节性细胞死亡途径，可能是导致各种病理状况的一个因素。尽管该领域的研究兴趣日益浓厚，但IgAN进展过程中控制铁死亡激活的确切分子途径仍不完全清楚，需要系统研究。本研究的目的是识别与铁死亡相关的特征基因（FFG），用于IgAN的潜在诊断，并研究其与肾免疫细胞浸润的关系。
从基因表达综合数据库（GEO）中检索IgAN患者和正常对照的肾组织微阵列数据集（GSE93798、GSE104948、GSE99339）。从铁死亡相关基因数据库中获取铁死亡相关基因。采用机器学习算法（套索回归、支持向量机递归特征消除、随机森林）筛选FFG。使用免疫组织化学和蛋白质印迹法在IgAN小鼠模型中验证研究结果。进行基因集富集分析（GSEA）以探索FFG在IgAN中的潜在机制。还通过CIBERSORT算法分析免疫细胞浸润特征。
在IgAN中总共鉴定出180个与铁死亡相关的差异表达基因。其中，双特异性磷酸酶1（DUSP1）通过三种机器学习算法被筛选为FFG。DUSP1在IgAN患者和小鼠的肾组织中均表现出显著下调。转录丰度增强与铁死亡相关生物标志物谷胱甘肽过氧化物酶4（GPX4）和胱氨酸/谷氨酸反向转运体（SLC7A11/xCT）呈显著正相关，而与酰基辅酶A合成酶长链亚型4（ACSL4）的表达呈负相关。GSEA进一步确定DUSP1在关键信号网络中的功能富集，特别是丝裂原活化蛋白激酶（MAPK）级联、ERBB受体酪氨酸激酶途径和Janus激酶-信号转导子（JAK-STAT）转导机制。免疫浸润分析表明，IgAN患者肾组织中T滤泡辅助细胞、活化的自然杀伤细胞和M1巨噬细胞的浸润增加，DUSP1表达与这些促炎细胞类型呈负相关。
我们的研究成功地将DUSP1鉴定为IgAN患者中与铁死亡相关的生物标志物，并探索了其在IgAN发病机制中的潜在机制及其与免疫细胞浸润的潜在关系。这些发现对IgAN患者的诊断和前瞻性治疗策略具有重要意义。
