Identifying and Validating Extracellular Matrix-Related Gene CTSH in Diabetic Foot Ulcer Using Bioinformatics and Machine Learning

Background: Diabetic foot ulcer (DFU) is a serious clinical problem with high amputation and mortality rates, yet there is a lack of desirable therapy.While the extracellular matrix (ECM) contributes significantly to wound healing, ECM-related biomarker for DFU is still unknown.The study was designed to identify ECM-related biomarker in DFU using bioinformatics and machine learning and validate it in STZ-induced mice models.Methods: GSE80178 and GSE134431 microarray datasets were fetched from the GEO database, and differentially expressed genes (DEGs) analysis was performed, respectively.By analyzing DEGs and ECM genes, we identified ECM-related DEGs, and functional enrichment analysis was conducted.Subsequently, three machine learning algorithms (LASSO, RF and SVM-RFE) were applied to filter ECM-related DEGs to identify key ECM-related biomarkers.Next, we conducted immune infiltration analysis, GSEA, and correlation analysis to explore the hub gene underlying mechanism.A lncRNA-miRNA-mRNA and drug regulatory network were constructed.Finally, we validated the key ECM-related biomarker in STZ-induced mice models.Results: One hundred and forty-five common DEGs in adult DFU between the two datasets were identified.Taking the intersection of 145 common DEGs and 964 ECM genes, we identified 13 ECM-related DEGs.Thirteen ECM-related DEGs were mainly enriched in pathways associated with tissue remodeling, inflammation and defense against infectious agents.Ultimately, CTSH was identified as the key ECM-related biomarker.CTSH was associated with difference immune cells during the occurrence and development of DFU, and it influenced hedgehog, IL-17 and TNF signaling pathway.Additionally, CTSH expression is correlated with many ECM-and immune-related genes.A lncRNA-miRNA-mRNA and drug regulatory network were constructed with 10 lncRNAs, 2 miRNAs, CTSH and 1 drug.Finally, CTSH was validated as a key biomarker for DFU in animal models.Conclusion: Our study found that CTSH can be used for both diagnostic and prognostic purposes and might be a potential therapeutic target.