Integrative analysis reveals ferroptosis-related genes with RRM2 as a key driver in endometriosis

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene Pub Date : 2025-09-10 DOI:10.1016/j.gene.2025.149754

Lanping Zhong , Yuhong Niu , Rui Ma , Yuting Luo , Xin Li , Qiru Wang , Hongxia Xu , Xiaomin Kang

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Abstract

Background

Endometriosis is an estrogen-dependent disorder with unclear molecular mechanisms. Ferroptosis, a regulated iron-dependent cell death, may play a key role, yet the specific genes involved remain underexplored.

Methods

Ferroptosis-related genes (FRGs) were identified in endometriosis using GEO data, with key genes selected through LASSO, SVM-RFE, and cross-tabulation analysis. We validated gene expression in the tissues of patients with endometriosis using quantitative real-time polymerase chain reaction (qRT-PCR) and assessed the causal effects of these genes on endometriosis subtypes through Mendelian randomization (MR). We further validated the causal relationship between FRGs with diagnostic value and the progression of endometriosis through in vitro and in vivo experiments.

Results

We identified 13 differentially expressed ferroptosis-related genes (DE-FRGs) in endometriosis, including six upregulated and seven downregulated genes. Among these, FZD7, HMOX1, HSPA5, TFAP2C, and RRM2 were identified as key genes with diagnostic potential (AUC =0.91). MR analysis revealed that FZD7, HMOX1, RRM2, and HSPA5 were causally associated with different subtypes of endometriosis, with FZD7 acting as a protective factor (OR < 1), while the others functioned as risk factors (OR > 1). Notably, RRM2 exhibited causal associations across multiple subtypes of the disease. qRT-PCR confirmed significant upregulation of RRM2 in ectopic endometrial tissues (P < 0.01). Functional validation experiments further demonstrated that RRM2 enhances the invasiveness of endometrial cells in vitro (P＜0.05), while in vivo, RRM2 overexpression induced endometriosis-like phenotypes in a mouse model.

Conclusion

Our integrative analysis combining transcriptomic profiling, MR, and experimental validation identified FRGs, particularly RRM2, as being causally associated with endometriosis. RRM2 may contribute to disease progression and represents a promising target for diagnosis and therapy.

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综合分析显示，与RRM2相关的铁中毒相关基因是子宫内膜异位症的关键驱动因素。

背景：子宫内膜异位症是一种雌激素依赖性疾病，分子机制尚不清楚。铁下垂是一种受调节的铁依赖性细胞死亡，可能在其中起关键作用，但涉及的特定基因仍未被充分研究。方法：利用GEO数据鉴定子宫内膜异位症中凋亡相关基因（DE-FRGs），并通过LASSO、SVM-RFE和交叉表列分析选择关键基因。我们利用qRT-PCR验证了患者组织中的基因表达，并通过mr评估了它们对子宫内膜异位症亚型的因果关系。我们通过体外和体内实验进一步验证了具有诊断价值的DE-FRGs与子宫内膜异位症进展之间的因果关系。结果：我们在子宫内膜异位症中鉴定了13个差异表达的铁中毒相关基因（DE-FRGs），包括6个上调基因和7个下调基因。其中，FZD7、HMOX1、HSPA5、TFAP2C和RRM2被鉴定为具有诊断潜力的关键基因（AUC > 0.7）。孟德尔随机化分析显示，FZD7、HMOX1、RRM2和HSPA5与不同亚型子宫内膜异位症存在因果关系（P  1）。值得注意的是，RRM2在该疾病的多个亚型中表现出因果关系。定量RT-PCR证实了RRM2在异位子宫内膜组织中的显著上调（P ）。结论：我们的综合分析结合转录组学分析、孟德尔随机化和实验验证，确定了铁中毒相关基因，特别是RRM2，与子宫内膜异位症有因果关系。RRM2可能促进疾病进展，是诊断和治疗的一个有希望的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Gene 生物-遗传学

CiteScore

6.10

自引率

2.90%

发文量

718

审稿时长

42 days

期刊介绍： Gene publishes papers that focus on the regulation, expression, function and evolution of genes in all biological contexts, including all prokaryotic and eukaryotic organisms, as well as viruses.