Bulk and Single‐Cell Transcriptome Analyses Unravel Gene Signatures of Mitochondria‐Associated Programmed Cell Death in Diabetic Foot Ulcer

Abstract

Mitochondrial programmed cell death (PCD) plays a critical role in the pathogenesis of diabetic foot ulcers (DFU). In this study, we performed a comprehensive transcriptome analysis to identify potential hub genes and key cell types associated with PCD and mitochondria in DFU. Using intersection analysis of PCD‐ and mitochondria‐related genes, we identified candidate hub genes through protein‐protein interaction and random forest analysis. At the single‐cell level, key cell types were further validated based on the expression of hub genes. Additionally, we explored the transcription factors (TFs) regulating hub gene expression and the cellular heterogeneity of DFU. Finally, the expression of key hub genes and TFs was validated in clinical specimens. Our results identified BCL2 and LIPT1 as significantly downregulated hub genes in DFU, with Keratinocytes, as the key cell type. Immunohistochemistry confirmed downregulation of BCL2 and LIPT1 in DFU samples (p < 0.05). Additionally, TFs CEBPD and IRF1 were significantly upregulated in DFU, as confirmed by real‐time polymerase chain reaction analysis (p < 0.05).