Uncovering the Interplay of Ferroptosis and Immune System in Coronary Artery Disease: Construction and Validation of a Diagnostic Model.

OBJECTIVE: To explore the roles of ferroptosis and immune regulation in coronary artery disease (CAD) and find potential diagnostic biomarkers. METHODS: Three gene expression profile datasets were used, with GSE202625 as the training set and GSE42148 and GSE180081 as validation sets. LIMMA identified differentially expressed genes (DEGs) between CAD and control groups. ClusterProfiler conducted functional enrichment analysis. Ferroptosis-related genes from FerrDb were intersected with DEGs. ssGSEA and Pearson analysis analyzed immune cell subsets. LASSO built a diagnostic model. In vitro and in vivo experiments included qPCR, ELISA, pathological examination, and Western blot. RESULTS: In the GSE202625 dataset, 70 genes were upregulated and 895 genes were downregulated in CAD samples. A total of 29 ferroptosis-associated DEGs were identified, and immune cell profiling revealed differences in immune cell subsets between CAD and healthy cohorts. LASSO identified six genes (IDH1, MMD, NDRG1, WIPI1, BID, and TRIM26) for the diagnostic model, which collectively achieved an AUC of 0.904 in the training dataset, 0.776 in the GSE180081 validation dataset, and 0.902 in the GSE42148 validation dataset. IDH1 had the highest diagnostic efficacy with an AUC of 0.821. Clinically, 26 CAD patients (angiographically confirmed, ≥50% luminal stenosis) and 12 controls showed that CAD patients had higher prevalence of hypertension, diabetes, and elevated lipid markers. IDH1 was downregulated in CAD patients and inversely correlated with the Gensini score. In the CAD mouse model, IDH1 expression was decreased in aortic tissues. CONCLUSION: Six genes correlated with CAD, and the multi-gene diagnostic model performed well. IDH1 was a potential CAD biomarker, aiding CAD diagnosis and treatment research.