Chadha Sonia
Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Lucknow, Uttar Pradesh, India.
Comput Biol Chem. 2025 Apr;115:108343. doi: 10.1016/j.compbiolchem.2025.108343. Epub 2025 Jan 7.
Endometriosis is an inflammatory disease, involving immune cell infiltration and production of inflammatory mediators. Ferroptosis has recently been recognized as a mode of controlled cell death and the iron overload and peroxidative environment prevailing in the ectopic endometrium facilitates the occurrence of ferroptosis. In the current investigation, gene expression data was obtained from the dataset GSE7305.The variation in infiltration of immune cells amongst the samples with endometriosis and normal tissue was analysed using the CIBERSORTx tool which revealed higher infiltration of T cells gamma delta, macrophages M2, B cells naïve, T cells CD4 memory resting cells, plasma cells, T cells CD8 and mast cells activated in the tissue samples with endometriosis. An overlap of the differentially expressed genes (DEGs) and ferroptosis related genes revealed 32 ferroptosis related DEGs (FR-DEGs). GO and KEGG pathway analysis showed the FR-DEGs to be enriched in ferroptosis. The PPI network of the FR-DEGs was constructed and TP53, HMOX1, CAV1, CDKN1A, CD44, EPAS1, SLC2A1, MAP3K5, GCLC and FANCD2 were identified as the hub genes. Pearson correlation revealed significant correlation between the hub genes and infiltrating immune cells in endometriosis, thereby suggesting existence of a regulatory crosstalk between immune responses and ferroptosis in endometriosis. Hub gene- miRNA network analysis revealed that 7 of the 10 hub genes were targets of 3 miRNAs -hsa-miR-20a-5p, hsa-miR-16-5p and hsa-miR-17-5p, thereby providing further insight into the regulatory mechanisms underlying disease progression. Predictive analysis and cross validation studies revealed TP53 and CDKN1A as common targets of hsa-miR-16-5p, hsa-miR-17-5p, and hsa-miR-20a-5p, thereby revealing their regulatory roles in ferroptosis and immune modulatory pathways relevant to endometriosis. The present study indicates an important role of both immune dysregulation and ferroptosis in the pathogenesis of endometriosis and identifies ferroptosis related hub genes and their miRNA regulators as favourable novel targets for further studies and therapeutic interventions.
子宫内膜异位症是一种炎症性疾病，涉及免疫细胞浸润和炎症介质的产生。铁死亡最近被认为是一种可控的细胞死亡方式，而异位子宫内膜中普遍存在的铁过载和过氧化环境促进了铁死亡的发生。在当前的研究中，基因表达数据来自数据集GSE7305。使用CIBERSORTx工具分析了子宫内膜异位症样本和正常组织样本中免疫细胞浸润的差异，结果显示在子宫内膜异位症组织样本中，γδT细胞、M2巨噬细胞、幼稚B细胞、静息CD4记忆T细胞、浆细胞、CD8 T细胞和活化肥大细胞的浸润较高。差异表达基因（DEG）与铁死亡相关基因的重叠分析揭示了32个与铁死亡相关的差异表达基因（FR-DEG）。基因本体（GO）和京都基因与基因组百科全书（KEGG）通路分析表明，FR-DEG在铁死亡中富集。构建了FR-DEG的蛋白质-蛋白质相互作用（PPI）网络，并确定TP53、血红素加氧酶1（HMOX1）、小窝蛋白1（CAV1）、细胞周期蛋白依赖性激酶抑制剂1A（CDKN1A）、CD44、内皮 PAS结构域蛋白1（EPAS1）、溶质载体家族2成员1（SLC2A1）、丝裂原活化蛋白激酶激酶激酶5（MAP3K5）、谷氨酸半胱氨酸连接酶催化亚基（GCLC）和范可尼贫血互补组D2（FANCD2）为枢纽基因。Pearson相关性分析显示，枢纽基因与子宫内膜异位症中浸润的免疫细胞之间存在显著相关性，从而表明子宫内膜异位症中免疫反应与铁死亡之间存在调节性相互作用。枢纽基因-微小RNA（miRNA）网络分析显示，10个枢纽基因中的7个是3种miRNA——hsa-miR-20a-5p、hsa-miR-16-5p和hsa-miR-17-5p的靶标，从而为疾病进展的潜在调控机制提供了进一步的见解。预测分析和交叉验证研究表明，TP53和CDKN1A是hsa-miR-16-5p、hsa-miR-17-5p和hsa-miR-20a-5p的共同靶标，从而揭示了它们在与子宫内膜异位症相关的铁死亡和免疫调节通路中的调控作用。本研究表明免疫失调和铁死亡在子宫内膜异位症发病机制中具有重要作用，并确定与铁死亡相关的枢纽基因及其miRNA调节因子是进一步研究和治疗干预的有利新靶点。
