Integrative bioinformatics and experimental validation identify IL1A as a novel therapeutic target for diabetic wound healing

Diabetic foot ulcers (DFUs) represent a severe complication of diabetes mellitus, characterized by impaired wound healing and persistent inflammation. Despite advances in understanding the molecular mechanisms underlying DFU pathogenesis, effective therapeutic targets remain limited. This study aimed to identify novel biomarkers and therapeutic targets for diabetic wound healing through integrative bioinformatics analysis and experimental validation. We performed comprehensive transcriptomic analysis of DFU samples (n = 6) compared to normal skin controls (n = 6) from the GEO database (GSE80178). Differential expression analysis, functional enrichment, gene set enrichment analysis (GSEA), and protein-protein interaction network analysis were conducted to identify hub genes. Key findings were validated through in vitro experiments using keratinocyte cell lines cultured under normal glucose (NG), low glucose (LG), and high glucose (HG) conditions, with functional assays including colony formation and scratch wound healing assays. We identified 8,269 differentially expressed genes (DEGs), including 1,852 upregulated and 6,417 downregulated genes in DFU samples. Functional enrichment analysis revealed significant alterations in skin development, keratinocyte differentiation, inflammatory responses, and IL-17 signaling pathways. Hub gene analysis identified interleukin-1 alpha (IL1A) as a central hub gene and a key inflammatory mediator (log2FC = 5.18, adjusted p < 0.001), participating in seven distinct biological pathways. Experimental validation demonstrated that high glucose conditions impaired keratinocyte colony formation and wound closure capacity, accompanied by dysregulated inflammatory responses, consistent with the bioinformatics predictions. Through integrative computational and experimental approaches, we identified IL1A as a critical therapeutic target in diabetic wound healing. Our findings provide mechanistic insights into DFU pathogenesis and establish IL1A as a promising biomarker for developing targeted interventions to improve diabetic wound healing outcomes.