Identification of Seven in absentia homolog 2 as a potential efferocytosis-related biomarker in diabetic foot ulcers.

INTRODUCTION: Wound of diabetic foot ulcers (DFU) is chronic and hard to heal, characterized by impaired inflammatory response, dysfunction of keratinocyte and endothelial cells and improper removal of dying cells. Efferocytosis, as a trigger for phenotype switch of macrophages, plays a critical role in diabetic foot wound healing. Here, we showed the effect of efferocytosis in wound healing of diabetics and identified seven in absentia homolog 2 (SIAH2) as a potential efferocytosis-related biomarker. METHODS: Blood and skin samples were collected from 20 patients diagnosed type II diabetes at Qilu Hospital of Shandong University. Efferocytosis related genes in DFU were identified based on GSE147890, GSE80178 datasets as well as RNA-seq data of blood samples. Enrichment analysis, clustering analysis and protein-protein interaction network analysis were conducted based on the efferocytosis related genes in DFU. An array diagram was constructed and survival analysis of DFU was performed based on the associated clinical data. Single-cell sequencing data analysis combined with experiments in vitro, we analyzed the role of SIAH2 in wound healing of DFU as well as its correlation with efferocytosis signal. RESULTS: Overall efferocytosis and SIAH2 expression level were increased in DFU blood and tissue samples and associated with poor survival in patients. Single-cell analysis revealed elevated SIAH2 expression is positively associated with keratinocyte migration, angiogenesis and efferocytosis of macrophage in wound healing of DFU. SIAH2 involved in efferocytosis-related cell-to-cell communication, especially in "internalization" and "digestion" signals. CONCLUSION: SIAH2 was identified to be one of the key efferocytosis genes and associated with poor prognosis of DFU. Protective upregulation of SIAH2 was involved in angiogenesis, keratinocyte migration and cell-to-cell communication mediated by efferocytosis in DFU wound healing.