New insights into diagnostic values and mechanisms of ferroptosis associated with immune infiltration in diabetic kidney disease

Abstract

The pathogenesis of diabetic kidney disease (DKD) is complex and closely related to ferroptosis and immune dysregulation, but the relevance is unclear.The present study investigates the potential mechanisms of ferroptosis-related genes (FRGs) in DKD and their relationship with the immune-inflammatory response.It searches for new diagnostic biomarkers to help diagnose and treat DKD.Four Gene Expression Omnibus (GEO) datasets, GSE30528, GSE30529 and GSE30122 as the test set, and GSE96804 for validation, were analyzed.FRGs were obtained from GeneCards, and 47 ferroptosis-related differentially expressed genes (FRDEGs) were identified by intersecting with DKD-related differentially expressed genes.Functional enrichment analyses, including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment Analysis and Gene Set Variation Analysis, revealed that these FRDEGs are primarily associated with ferroptosis, hypoxia response and immune inflammation.Subsequently, the weighted gene co-expression network analysis (WGCNA) was employed to expand the ferroptosis-related gene network, and intersection of the 47 FRDEGs with key WGCNA module genes yielded 10 key genes.Based on the 10 key genes, the least absolute shrinkage and selection operator and support vector machine algorithms identified three hub genes [chemokine ligand 5 (CCL5), forkhead box C1 (FOXC1) and lactotransferrin (LTF)] for DKD diagnosis.Receiver operating characteristic curves confirmed their diagnostic value, with FOXC1 and LTF validated in the independent dataset.Immune infiltration analysis via CIBERSORT revealed eight immune cell types with significantly different infiltration levels between the DKD and control group in the integrated GEO datasets.Notably, both LTF and CCL5 showed a significant positive correlation with gamma delta T cells (γδT).Quantitative PCR results confirmed differential expression of the three hub genes in the DKD group, with elevated expression observed in DKD mice following intervention with rosiglitazone and hyperoside.