Identification and Correlation Analysis of Ferroptosis-Related Genes in Three Brain Regions of Patients with Schizophrenia

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.