Dai Shiqin, Xu Yong, Yang Tingting, Wang Feng, Jiang Yihua
Prevention and Treatment Department, Shanghai Minhang District Mental Health Center, 201112 Shanghai, China.
School of Life Sciences, East China Normal University, 200241 Shanghai, China.
Actas Esp Psiquiatr. 2024 Dec;52(6):800-809. doi: 10.62641/aep.v52i6.1740.
Schizophrenia (SZ) is a severe mental disorder that is marked by hallucinations and cognitive impairments. Ferroptosis is a type of cell death that is associated with iron and lipid peroxidation; it may play a role in SZ etiology. The present study aimed to explore the correlations between ferroptosis-related genes and SZ in three brain regions.
We used the Gene Expression Omnibus dataset GSE80655 to analyze brain samples from SZ patients and controls; specifically, we evaluated the anterior cingulate cortex (Ancg), dorsolateral prefrontal cortex (DLPFC), and nucleus accumbens (nAcc). The data were preprocessed in R, and ferroptosis-related differentially expressed genes (DEGs) were identified. Pearson correlation analysis was then performed to assess correlations between these DEGs and age at death, postmortem interval, or brain pH. To identify important ferroptosis-related genes, we created a protein-protein interaction network using the Search Tool for the Retrieval of Interacting Genes/Proteins database, and visualized it using Cytoscape software. Moreover, the pROC package was used to calculate the area under the receiver operating characteristic curves for these important genes. Finally, gene set variation analysis was used for the pathway enrichment analysis of ferroptosis-related pathways, followed by the Wilcoxon rank-sum test.
Nine ferroptosis-related DEGs were upregulated in the Ancg region and one was downregulated in the nAcc region. In the Ancg region, the SZ group had four ferroptosis-related DEGs that were negatively correlated with postmortem interval, and the control group had five ferroptosis-related DEGs that were negatively correlated with brain pH. The protein-protein interaction network analysis of the Ancg region revealed seven significant interacting genes; tissue inhibitor of metalloproteinases 1 (TIMP1) and galectin 3 (LGALS3) were the hub genes. Gene set variation analysis revealed substantial changes in the glycolysis pathway in the Ancg region, and in the glutamate transmembrane transport pathway and unsaturated fatty acid biosynthesis process pathway in the nAcc region, in SZ patients compared with controls.
The correlation between ferroptosis and SZ appears to be stronger in the Ancg than in the nAcc or dorsolateral prefrontal cortex. This association may be mediated by TIMP1 and LGALS3 as well as by the glycolysis pathway, indicating that these might be possible biomarkers for SZ.
精神分裂症（SZ）是一种严重的精神障碍，其特征为幻觉和认知障碍。铁死亡是一种与铁和脂质过氧化相关的细胞死亡类型；它可能在精神分裂症的病因学中起作用。本研究旨在探讨三个脑区中铁死亡相关基因与精神分裂症之间的相关性。
我们使用基因表达综合数据库GSE80655分析精神分裂症患者和对照组的脑样本；具体而言，我们评估了前扣带回皮质（Ancg）、背外侧前额叶皮质（DLPFC）和伏隔核（nAcc）。数据在R中进行预处理，并鉴定出铁死亡相关的差异表达基因（DEGs）。然后进行Pearson相关性分析，以评估这些DEGs与死亡年龄、死后间隔或脑pH值之间的相关性。为了鉴定重要的铁死亡相关基因，我们使用检索相互作用基因/蛋白质的搜索工具数据库创建了一个蛋白质-蛋白质相互作用网络，并使用Cytoscape软件对其进行可视化。此外，使用pROC软件包计算这些重要基因的受试者工作特征曲线下面积。最后，使用基因集变异分析对铁死亡相关途径进行通路富集分析，随后进行Wilcoxon秩和检验。
在Ancg区域有9个铁死亡相关的DEGs上调，在nAcc区域有1个下调。在Ancg区域，精神分裂症组有4个铁死亡相关的DEGs与死后间隔呈负相关，对照组有5个铁死亡相关的DEGs与脑pH值呈负相关。Ancg区域的蛋白质-蛋白质相互作用网络分析揭示了7个显著的相互作用基因；金属蛋白酶组织抑制剂1（TIMP1）和半乳糖凝集素3（LGALS3）是枢纽基因。基因集变异分析显示，与对照组相比，精神分裂症患者Ancg区域的糖酵解途径、nAcc区域的谷氨酸跨膜转运途径和不饱和脂肪酸生物合成过程途径有显著变化。
铁死亡与精神分裂症之间的相关性在Ancg区域似乎比在nAcc或背外侧前额叶皮质更强。这种关联可能由TIMP1和LGALS3以及糖酵解途径介导，表明这些可能是精神分裂症的潜在生物标志物。
