Integrated Multi-Omics and Independent Validation Reveal MPO and TREM2 as Secretory Biomarkers for Non-Healing Diabetic Foot Ulcers

作者：Xiaotian Li, T Li, J.R. Wang, Lei Gao · 发表于：Genes · 年份：2025 · DOI：10.3390/genes16121419 · 被引用次数：2 · 研究领域：Inflammation biomarkers and pathways、Wound Healing and Treatments、Diabetic Foot Ulcer Assessment and Management

Background: Diabetic foot ulcers (DFUs) are chronic wounds with high morbidity and mortality. Secretory proteins coordinate intercellular communication and may regulate inflammation, tissue repair and regeneration, but their contributions to DFU pathogenesis remain unclear. Aim: To discover and validate secretory protein–linked biomarkers that distinguish non-healing DFUs and to explore their potential utility for diagnosis and therapy. Methods: We integrated bulk RNA-sequencing datasets (GSE199939 training set; GSE80178 and GSE143735 validation sets) and a single-cell RNA-sequencing dataset (GSE223964). Differentially expressed genes, secretory protein lists, and weighted gene co-expression networks were intersected to select candidates. Functional enrichment, protein interaction networks and support vector machine–recursive feature elimination identified key markers. We visualized their cell-type distribution at single-cell resolution and validated their expression in external cohorts. Pathway enrichment, gene co-expression networks, ceRNA regulatory analysis and qRT-PCR in patient samples were used for further characterization. Results: Among 4803 differentially expressed genes, 743 overlapped with known secretory proteins. WGCNA highlighted modules strongly associated with DFUs, yielding 386 candidates. SVM-RFE combined with protein interaction analysis pinpointed four secretory proteins—LYZ, MPO, SLCO2B1 and TREM2—as putative biomarkers. Single-cell analyses showed that ...