Cellular senescence-related gene signatures as predictive markers and regulatory mechanisms in diabetic foot ulcers

Diabetic foot ulcer (DFU) is a serious complication of diabetes. Cellular senescence has been increasingly recognized as a key contributor to delayed wound healing in DFU, but its specific molecular mechanisms remain unclear. We integrated transcriptomic datasets and senescence-related genes to identify differentially expressed hub genes using LASSO and random forest algorithms. A diagnostic model was constructed and validated. Single-cell RNA sequencing (scRNA-seq) and immune infiltration analyses were performed to explore cellular localization and immune correlations. Senescence was induced in fibroblasts and keratinocytes using H₂O₂, followed by β-galactosidase staining and qPCR for validation. Senescence markers (e.g., p21, IL6, MMP1) were elevated in DFU tissues. Four hub genes—EGFR, RAD51, CCNA2, and SUN1—were identified and used to build a predictive model with high diagnostic accuracy (AUC > 0.85). scRNA-seq revealed their expression in fibroblasts, keratinocytes, and macrophages. These genes were associated with inflammatory pathways and immune cell infiltration. In vitro experiments confirmed their altered expression in senescent skin cells. Cellular senescence plays a critical role in DFU, with EGFR, RAD51, CCNA2, and SUN1 serving as potential diagnostic biomarkers and therapeutic targets. Targeting senescence may provide new strategies for DFU management.