Multi-omics and experimental validation identify methylation-related genes and METTL16 as key regulators in diabetic foot ulcer pathogenesis

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Diabetic foot ulcers (DFUs) are a severe complication of diabetes, characterized by impaired wound healing, chronic inflammation, and tissue degradation. N 6 -methyladenosine (m 6 A), has emerged as a critical regulator in gene expression and cellular function in wound healing. This study aimed to systematically investigate the role of methylation-related genes (MRGs) in DFU pathogenesis, focusing on their diagnostic and therapeutic potential through integrative multi-omics analysis and experimental validation. Publicly available bulk RNA-seq, microarray, and single-cell RNA sequencing (scRNA-seq) datasets were analyzed to identify differentially expressed MRGs (DE-MRGs). Machine learning algorithms (LASSO, GBM, SVM-RFE, Random Forest) were used to screen key biomarkers. Immune infiltration and pathway enrichment analyses characterized inflammatory signatures, while scRNA-seq mapped MRG dynamics across cell types. Functional assays validated the role of METTL16 in high glucose-treated human skin fibroblasts (HSFs), assessing collagen synthesis, oxidative stress, and cellular migration. Thirteen DE-MRGs were identified in DFU tissues, with METTL16, NSUN3, and IGF2BP2 prioritized as diagnostic biomarkers. Immune profiling revealed M1 macrophage enrichment and dysregulated IL-17/MAPK pathways. Single-cell analysis highlighted METTL16's dynamic role in fibroblast activation and int

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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