Integrated Bulk and Single-Cell Transcriptomics Reveals Cell-Type-Specific Fatty Acid Metabolic Dysregulation and Candidate Biomarkers in Diabetic Foot Ulcers.

BACKGROUND AND OBJECTIVE: Diabetic foot ulcers (DFUs) are debilitating complications of diabetes, leading to severe health outcomes and high healthcare costs. Understanding the molecular mechanisms is crucial for better management. This study aims to explore the roles of fatty acid metabolism (FAM) and the immune landscape in DFUs to identify potential diagnostic biomarkers and therapeutic targets. METHODS: Single-cell RNA sequencing (scRNA-seq) data from GSE165816 were analyzed to assess cellular diversity within DFU tissues. GSE7014 and GSE134431 were utilized for differential gene expression and FAM profiling. The study employed fatty acid oxidation (FAO) and synthesis (FAS) evaluations, immune cell infiltration analysis using CIBERSORT, and bioinformatics to delineate FAM-related marker genes. RESULTS: Results indicated elevated FAM levels in DFU compared to healthy skin in scRNA-seq data. Notably, the pronounced increase of FAO in DFU tissues suggested a metabolic adaptation possibly beneficial for energy supply in the harsh ulcer environment. Conversely, FAS was significantly diminished in DFU. Immune profiling unveiled a skewed infiltration pattern with an increased presence of pro-inflammatory M1 macrophages and a decreased anti-inflammatory M2 macrophages, reinforcing the role of inflammation in DFU pathology. Moreover, integration of differential expression analysis with FAM-related genes identified four candidate biomarkers with high transcriptomic discriminatory performance for distinguishing DFU from control samples. These four genes are closely linked to a diverse array of immune cells and functions. CONCLUSION: The study reveals an association between FAM dysregulation and immune imbalance in DFUs and identifies candidate diagnostic biomarkers and potential therapeutic targets, providing new insights into the metabolic-immune landscape of diabetic foot ulcers.