Identification of Markers for Diagnosis and Treatment of Diabetic Kidney Disease Based on the Ferroptosis and Immune

Abstract

Background: In advanced diabetic kidney disease (DKD), iron metabolism and immune dysregulation are abnormal, but the correlation is not clear. Therefore, we aim to explore the potential mechanism of ferroptosis-related genes in DKD and their relationship with immune inflammatory response and to identify new diagnostic biomarkers to help treat and diagnose DKD.

Methods: Download data from gene expression omnibus (GEO) database and FerrDb database, and construct random forest tree (RF) and support vector machine (SVM) model to screen hub ferroptosis genes (DE-FRGs). We used consistent unsupervised consensus clustering to cluster DKD samples, and enrichment analysis was performed by Gene Set Variation Analysis (GSVA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) and then assessed immune cell infiltration abundance using the single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT algorithms. Ferroptosis scoring system was established based on the Boruta algorithm, and then, core compounds were screened, and binding sites were predicted by Coremine Medical database.

Results: We finally established a 7-gene signature (DUSP1, PRDX6, PEBP1, ZFP36, GABARAPL1, TSC22D3, and RGS4) that exhibited good stability across different datasets. Consistent clustering analysis divided the DKD samples into two ferroptosis modification patterns. Meanwhile, autophagy and peroxisome pathways and immune-related pathways can participate in the regulation of ferroptosis modification patterns. The abundance of immune cell infiltration differs significantly across patterns. Further, molecular docking results showed that the core compound could bind to the protein encoded by the core gene.

Conclusions: Our findings suggest that ferroptosis modification plays a crucial role in the diversity and complexity of the DKD immune microenvironment, and the ferroptosis score system can be used to effectively verify the relationship between ferroptosis and immune cell infiltration in DKD patients. Kaempferol and quercetin may be potential drugs to improve the immune and inflammatory mechanisms of DKD by affecting ferroptosis.