Diagnostic and therapeutic biomarker discovery in diabetic foot ulcers: an integrative analysis linking hypoxia and cuproptosis

Diabetic foot ulcer (DFU), a severe complication of diabetes, is driven by hypoxia and impaired cell metabolism. The crosstalk between hypoxia and the newly defined copper-dependent cell death (cuproptosis) in DFU remains unknown. We aimed to identify key biomarkers at this intersection for diagnosis and therapy. We integrated transcriptomic data (GSE134431) with cuproptosis and hypoxia gene sets. Machine learning (XGBoost) screened for core genes, validated in an independent cohort (GSE80178). Diagnostic models were built and assessed via ROC curves and nomograms. Functional enrichment, regulatory networks, and drug predictions were performed bioinformatically. RT-qPCR validated findings in clinical DFU tissues. Thirty-one hub genes linking hypoxia and cuproptosis were identified. Three genes—BCL2, CA12, and CP—emerged as robust biomarkers. A diagnostic model based on them showed high accuracy (AUC > 0.7). They were functionally linked to apoptosis, spliceosome, and lysine degradation. BCL2 and CP were enriched in endothelial cells, correlating with DFU-associated angiogenesis defects. Drug prediction suggested ferulic acid (targeting CA12) and deferiprone (targeting CP) as potential therapeutics. RT-qPCR confirmed significant downregulation of BCL2 and CP in DFU samples. We unveil a novel molecular network coupling hypoxia and cuproptosis in DFU, and nominate BCL2, CA12, and CP as promising diagnostic biomarkers and therapeutic targets, offering new avenues for precise DFU management.