铁死亡相关基因对溃疡性结肠炎具有诊断预测价值

doi:10.12122/j.issn.1673-4254.2025.09.12

南方医科大学学报 ›› 2025, Vol. 45 ›› Issue (9): 1927-1937.doi: 10.12122/j.issn.1673-4254.2025.09.12

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铁死亡相关基因对溃疡性结肠炎具有诊断预测价值

何榕茂¹(), 方泽扬¹, 张芸芸¹, 吴友谅¹, 梁世秀², 计涛³, 陈科全¹, 王斯琪¹()

^1.广州医科大学附属第一医院，消化内科，广东广州 510120
^2.广州医科大学附属第一医院，变态反应科，广东广州 510120
^3.中山大学附属第六医院胃肠外科，广东广州 510000

收稿日期:2025-02-23 出版日期:2025-09-20 发布日期:2025-09-28
通讯作者: 王斯琪 E-mail:hrm715821@163.com;2023681011@gzhmu.edu.cn
作者简介:何榕茂，在读硕士研究生，E-mail: hrm715821@163.com
基金资助:
国家自然科学青年基金(82500630);国家自然科学青年基金(82300032);广东省基础与应用基础研究基金省市联合基金(2023A1515110161);广州市科学技术局基础研究计划基础与应用基础研究专题项目(2024A04J3537);广州市科技局基础研究计划市校（院）联合资助“登峰医院”项目(2024A03J1145);广州医科大学科研能力提升提升计划

Diagnostic and predictive value of ferroptosis-related genes in patients with ulcerative colitis

Rongmao HE¹(), Zeyang FANG¹, Yunyun ZHANG¹, Youliang WU¹, Shixiu LIANG², Tao JI³, Kequan CHEN¹, Siqi WANG¹()

^1.Department of Gastroenterology, Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China
^2.Department of Allergy, First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China, Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China
^3.Department of Gastrointestinal Surgery, Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China

Received:2025-02-23 Online:2025-09-20 Published:2025-09-28
Contact: Siqi WANG E-mail:hrm715821@163.com;2023681011@gzhmu.edu.cn
Supported by:
Youth Program of National Natural Science Foundation of China(82500630)

摘要/Abstract

摘要：

目的探讨铁死亡相关基因在溃疡性结肠炎（UC）诊断和预测中的的价值。方法本研究从GEO数据库中选择UC数据集，筛选差异表达基因（DEGs），进一步从“FerrDb“数据库中筛选与铁死亡相关的DEGs并进行功能分析。通过构建蛋白-蛋白相互作用网络（PPI）筛选枢纽基因，采用CIBERSORT评估UC与对照组的免疫浸润水平差异，以及利用训练集验证枢纽基因在UC诊断中的价值。进一步通过构建UC小鼠模型，利用实时荧光定量PCR （qPCR）检测小鼠结肠中枢纽基因的表达情况。结果筛选到76个与铁死亡相关的差异表达基因。功能富集分析显示铁死亡和缺氧途径显著富集。蛋白相互作用网络确定了10个枢纽基因，经数据库验证有9个枢纽基因在UC中高表达。经免疫细胞浸润分析显示，27种细胞类型在UC中明显升高（P<0.05），免疫检查点相关基因均与枢纽基因PPARG相关性最强（P<0.05）。进一步通过训练集验证P4HB、PPARG、STAT3在疾病中预测价值最佳（P<0.05）。通过构建小鼠UC模型验证结肠组织中枢纽基因的表达水平，RT-PCR显示与对照组相比，UC模型中PPARG表达明显降低，P4HB、STAT3表达明显升高（P<0.05）。结论铁死亡相关基因在UC的诊断预测中具有重要价值。

关键词: 溃疡性结肠炎, 铁死亡, 免疫浸润, PPARG, T细胞

Abstract:

Objective To explore the value of ferroptose-related genes in the diagnosis and prediction of ulcerative colitis (UC). Methods We used UC dataset from the GEO database to screen for differentially expressed genes (DEGs) in UC. The DEGs related to ferroptositis were screened from the FerrDb database and their functions were analyzed. The hub genes were identified by constructing the protein-protein interaction network (PPI), the differences in immune infiltration levels between UC and the control group were evaluated using CIBERSORT, and the diagnostic values of the hub genes for UC were verified by using the training set. In a mouse model of UC, we examined the expression levels of the hub genes in the colon tissues of the mice using real-time fluorescence quantitative PCR (qPCR). Results We identified a total of 76 DEGs related to ferroptosis. Functional enrichment analysis showed that these genes were significantly enriched in ferroptosis and hypoxia pathways. The PPI network identified 10 hub genes, and 9 of them were highly expressed in UC. Analysis of immune cell infiltration showed that 27 cell types were significantly increased in UC (P<0.05), and the immune checkpoints-related genes had the strongest correlation with the hub gene PPARG (P<0.05). Verification analysis using the training set showed that P4HB, PPARG and STAT3 had the best predictive value for UC (P<0.05). In the UC mouse model, the expression of PPARG was significantly decreased and the expressions of P4HB and STAT3 were significantly increased in the colon tissues of the mice as compared with the normal mice. Conclusion Ferroptose-related genes have significant value for diagnosis and prediction of UC.

Key words: ulcerative colitis, ferroptosis, immune infiltration, PPARG, T cells

何榕茂, 方泽扬, 张芸芸, 吴友谅, 梁世秀, 计涛, 陈科全, 王斯琪. 铁死亡相关基因对溃疡性结肠炎具有诊断预测价值[J]. 南方医科大学学报, 2025, 45(9): 1927-1937.

Rongmao HE, Zeyang FANG, Yunyun ZHANG, Youliang WU, Shixiu LIANG, Tao JI, Kequan CHEN, Siqi WANG. Diagnostic and predictive value of ferroptosis-related genes in patients with ulcerative colitis[J]. Journal of Southern Medical University, 2025, 45(9): 1927-1937.

图/表 10

表1 引物序列

Tab.1 Primers sequences for qPCR

Primer	Sequence
GPX4-F	GATGGAGCCCATTCCTGAACC
GPX4-R	CCCTGTACTTATCCAGGCAGA
NOX1-F	GGTTGGGGCTGAACATTTTTC
NOX1-R	TCGACACACAGGAATCAGGAT
CYBB-F	TGTGGTTGGGGCTGAATGTC
CYBB-R	CTGAGAAAGGAGAGCAGATTTCG
PTGS2-F	TTCAACACACTCTATCACTGGC
PTGS2-R	AGAAGCGTTTGCGGTACTCAT
HIF-1A-F	ACCTTCATCGGAAACTCCAAAG
HIF-1A-R	CTGTTAGGCTGGGAAAAGTTAGG
ACSL1-F	TGCCAGAGCTGATTGACATTC
ACSL1-R	GGCATACCAGAAGGTGGTGAG
SMAD7-F	GGCCGGATCTCAGGCATTC
SMAD7-R	TTGGGTATCTGGAGTAAGGAGG
CD44-F	TCGATTTGAATGTAACCTGCCG
CD44-R	CAGTCCGGGAGATACTGTAGC
PPARG-F	GGAAGACCACTCGCATTCCTT
PPARG-R	GTAATCAGCAACCATTGGGTCA

图1 UC患者与对照组铁死亡相关差异基因分析

Fig.1 Differentially expressed genes (DEGs) associated with iron death in UC patients and control subjects. A: Volcano maps of differential gene expressions in UC and control groups. B: Intersection of the DEGs and the genes associated with ferroptosis in UC and control groups. C: Heat maps of the DEGs associated with ferroptosis in UC and control groups. D: Classification of the 76 DEGs associated with ferroptosis, including 41 driver genes, 38 suppressor genes, and 2 marker genes.

图2 UC患者和对照组中铁死亡相关DEGs富集分析

Fig.2 Analysis of DEGs enrichment in relation to ferroptosis in UC and control groups. A: KEGG path in UC and control groups. B: Main biological processes of the DEGs in UC patients and control group. C: Main cell components of the DEGs in UC patients and control group. D: Main molecular functions of the DEGs in UC patients and control group.

图3 UC患者和对照组与铁死亡相关DEGs PPI分析

Fig.3 PPI analysis of the DEGs associated with ferroptosis in UC and controls. A: PPI network of the DEGs associated with ferroptosis in UC and controls. B: MCC algorithm for screening the main hub gene network.

图4 UC与对照组之间的免疫检查点和免疫浸润差异分析

Fig.4 Analysis of the differences in immune checkpoint and immune infiltration between UC and control groups in the dataset. A: Differential expression of 8 immune checkpoint genes between UC and control group. **P<0.01,***P<0.001, ****P<0.0001 (Control group vs UC group). B: Differences in 28 different types of immune cells between UC patients and controls.

图5 枢纽基因与免疫检查点基因及免疫细胞的关系

Fig.5 Relationship between pivot genes, immune checkpoint genes and immune cells. A: Pearson correlation analysis of the correlations of the hub gene with immune checkpoint gene in UC and control groups. B: CIBERSORT algorithm for assessing the correlation between the key genes and 28 immune cell types in UC and control group. *P<0.05, **P<0.01, ***P<0.001.

图6 UC训练集中10个枢纽基因诊断价值

Fig.6 Analysis of the diagnostic values of the hub genes for UC using the training set. A: Expression differences of 10 hub genes between UC group and control group. ****P<0.0001, Control group vs UC group. B: ROC curves of the 10 hub genes for UC diagnosis.

图7 验证集中10个枢纽基因预测UC价值

Fig.7 Verification of the value of the 10 hub genes for predicting UC. A: Differences in the expression of 10 hub genes between UC group and control group. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 (Control group vs UC group). B: ROC curve of the 10 hub genes for predicting UC.

图8 对照组UC模型小鼠模型结肠枢纽基因表达情况

Fig.8 Hub gene expressions in the colon tissues of the UC mouse model. A: Comparison of disease activity index (DAI) between control and UC mice. B: HE staining of the colon tissue in control and UC mice (Scale bar=50 μm). C: Comparison of the expression levels of the 10 hub genes in the colon tissues between control and UC mice. *P<0.05, **P<0.01, ***P<0.001 vs NC group.

图9 小鼠结肠铁死亡相关基因表达和组织炎症评分的相关性分析

Fig.9 Correlation analysis of colonic ferroptosis-related gene expression andtissue inflammation score in mice.

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铁死亡相关基因对溃疡性结肠炎具有诊断预测价值

Diagnostic and predictive value of ferroptosis-related genes in patients with ulcerative colitis

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