STAT3 Contributes to Wound Healing in Diabetic Foot Ulcer by Targeting the CHI3L1/MAPK Axis

Abstract

Background: Diabetic foot ulcer (DFU), characterized by delayed wound healing, is a severe complication of diabetes mellitus. A report using single-cell sequencing technology revealed increased chitinase 3 like 1 (CHI3L1)-overexpressing fibroblasts in DFU patients with wound healing. Therefore, this study aimed to elucidate the role and mechanism of CHI3L1 in wound-healing process during DFU. Methods: DFU model rats were constructed with streptozotocin injection and scald wound formation. Subsequently, the rats were administered with adeno associated virus to overexpress signal transducer and activator of transcription 3 (STAT3). Human dermal fibroblasts (HDFs) were transfected with recombinant constructs as needed. Moreover, the binding of STAT3 to CHI3L1 was determined through bioinformatics analysis and dual-luciferase reporter assay. The trauma area, pathological changes, cell viability, migration, and protein levels of hypoxia-inducible factor-1 (HIF-1α), vascular endothelial growth factor (VEGF), and STAT3/CHI3L1/mitogen-activated protein kinase (MAPK) axis were assessed. Results: STAT3 overexpression significantly reduced trauma area and increased levels of HIF-1α and VEGF and the number of new vessels in DFU rats (p < 0.001). Moreover, overexpression of STAT3 enhanced proliferation, migration, VEGF secretion, and the expression levels of HIF-1α, VEGF, STAT3, CHI3L1, and phosphorylated p38 MAPK (p-p38) in DFU rats and HDFs (p < 0.001). STAT3 might bind with CHI3L1 in HDFs. The effect of CHI3L1 silencing on HDFs was opposite to that of STAT3 overexpression (p < 0.05). However, CHI3L1 silencing reversed the role of STAT3 overexpression (p < 0.001). Conclusion: STAT3 upregulation accelerates wound healing by promoting the proliferation and migration of fibroblasts by activating the CHI3L1/MAPK axis. These findings provide new drug targets for DFU treatment and unveil the underlying mechanism of delayed wound healing in DFU.