ETS1 Expression in Diabetic Foot Ulcers: Implications for Fibroblast Phenotype and Wound Healing Through the PP2A/YAP Pathway

Wenjuan Yi,1 Qionglin Bao,2 Dingkun Xu,3 Chenyu Long,1 Ruixin Fang,1 Wenlin Cheng,4 Jiquan Song,1 Huiting Feng1 1Department of Dermatology, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Wound Repair Center, Chronic Wound and Diabetic Foot Clinical Medical Research Center, Liyuan Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, People’s Republic of China; 4Department of Cardiology, Zhongnan Hospital, Wuhan University, Wuhan, People’s Republic of ChinaCorrespondence: Huiting Feng; Jiquan Song, Email feng_huiting@126.com; songjiq@126.comObjective: Diabetic foot ulcers (DFUs) are a serious complication of diabetes, characterized by impaired wound healing and high morbidity and mortality risks. While ETS1 is known to influence fibroblast pathological remodeling, its specific role in DFU and fibroblast wound healing remains unclear.Methods: Skin tissue samples from DFU patients were categorized by Wagner grades to analyze ETS1 expression. Primary fibroblasts derived from diabetes mellitus wound (DMFBs) were collected from wound margins to test migration ability and analyze cell phenotype by immunofluorescence; they were further treated with siETS1 and the ETS1 inhibitor YK-4-279. Techniques including Western blotting, quantitative Real-Time PCR (qRT-PCR), and immunofluorescence were used to assess the expressionof ETS1, Collagen I, and phenotype in DMFBs. Additionally, the binding sites between human ETS1 and the PP2A promoter were predicted by the UCSC and JASPAR databases. It intended to explore the negative transcriptional regulation of PP2A by ETS1 and its implications in fibroblast function and wound healing.Results: Fibroblasts derived from Wagner Grades II–IV exhibit differences in cell morphology, migratory ability, and phenotype. Our findings indicate a significant upregulation of ETS1 in Wagner III and IV. The downregulation of ETS1 was observed to enhance DMFB migration and increase the expression of Collagen I and α-SMA. These changes suggest a potential mechanism by which PP2A regulates the YAP/Hippo pathway in diabetic wound healing.Conclusion: ETS1 appears to impede the repair processes in DFUs, likely through the negative regulation of PP2A, affecting fibroblast function and wound healing.Keywords: diabetic wound, diabetic foot ulcer, ETS1, PP2A, YAP