HIF1A-Associated Ferroptosis-Related Gene Signatures Reveal Candidate Circulating Biomarkers in Diabetic Nephropathy

Diabetic nephropathy (DN) is a major microvascular complication of diabetes. Hypoxia-inducible factor 1-alpha (HIF1A) and ferroptosis contribute to the progression of DN, but the circulating biomarkers associated with these pathways are still unknown. In this study, the whole-blood transcriptomic datasets in the Gene Expression Omnibus were combined with ferroptosis-related genes from the FerrDb database and published literature. The differentially expressed genes of HIF1A and of DN were intersected, and then the feature selection with Boruta and SVM-RFE was performed, followed by external validation, immune infiltration analysis, prediction of regulatory network, drug-target prediction, and RT-qPCR validation. We identified 773 HIF1A-related genes, 1445 DN-related genes, and 22 overlapping candidate genes. Using machine-learning analysis, nine core genes were identified, including SLC7A5 and SLC2A14, which consistently upregulated in both training and validation datasets and corroborated by RT-qPCR. Both genes were positively associated with activated natural killer cells and negatively associated with monocytes in estimated circulating immune-cell composition analysis. Regulatory-network and DrugBank analyses generated hypotheses regarding upstream miRNAs and potential compound interaction. These findings identify SLC7A5 and SLC2A14 as candidate circulating biomarkers related to HIF1A expression and ferroptosis-related gene signatures in DN. Further large-cohort and functional studies are required to confirm their diagnostic and mechanistic relevance.