Based on Bioinformatics Analysis of Ferroptosis-Immune Interaction Core Genes and Immune Infiltration Characteristics in Alzheimer’s Disease

Abstract

Objective: This study aims to systematically screen the core genes co-regulated by ferroptosis and immunity in Alzheimer’s disease (AD) through bioinformatics analysis, construct a multi-level molecular network, provide a theoretical basis for revealing the molecular mechanism of the interaction between ferroptosis and the immune microenvironment in AD, enrich the pathological connotation of neuroinflammation and iron metabolism disorders, and offer potential intervention targets and new research ideas for the diagnosis and immune-targeted therapy of AD. Methods: The GSE5281 dataset was downloaded from the Gene Expression Omnibus (GEO) as the analysis object. The limma package in the R language was used to screen differentially expressed genes (DEGs). Intersection genes between ferroptosis-related and immunity-related DEGs were obtained by cross-referencing with the FerrDb and ImmPort databases. Subsequently, GO and KEGG enrichment analyses were performed to elucidate the functions and pathways of the candidate genes. To visualize protein-protein interactions, STRING, Cytoscape, and Cytohubba were used to construct a protein-protein interaction network and screen core hub genes. The CIBERSORT algorithm was employed to estimate the infiltration abundance of 22 immune cell types, generate stacked bar plots, and compare immune infiltration levels between the AD and control groups using the Wilcoxon test with FDR multiple-testing correction; intergroup differences were displayed via boxplots. Results: Intersecting the 1191 DEGs from the GSE5281 dataset with ferroptosis and immunity gene sets yielded 54 ferroptosis-immunity intersection DEGs. Functional enrichment analysis showed that these genes were predominantly involved in negative regulation of immune system processes, monocyte differentiation, lymphocyte proliferation, and vesicle lumen components, and were significantly enriched in the TNF signaling pathway, lipid metabolism-related pathways, and immune inflammation-related pathways. Topological analysis of the PPI network using Cytoscape and the MCC algorithm in CytoHubba identified five core hub genes: BCL2, CD44, FOXO1, PPARG, and SOX2. Immune infiltration stacked bar plots showed marked differences in immune cell composition between the AD and control groups, with the AD group exhibiting an overall shift toward a pro-inflammatory, activated immune state. After FDR correction, boxplots further demonstrated that, compared with the control group, the AD group had significantly elevated infiltration proportions of memory B cells, CD8 + cytotoxic T cells, eosinophils, and neutrophils (P Conclusion: This study screened and identified five core hub genes for ferroptosis-immune interaction in AD: BCL2, CD44, FOXO1, PPARG, and SOX2. Functional enrichment revealed their significant involvement in immune inflammation-related pathways such as the TNF signaling pathway and lipid metabolism. Immune infiltration analysis found that AD brain tissue exhibits microenvironment remodeling characterized by increased infiltration of pro-inflammatory immune cells and decreased resting innate immune cells. These findings provide new molecular target combinations and a theoretical basis for the early diagnosis of AD and combined immune-ferroptosis targeted therapy.