Liao Xincheng, Jiang Zhengying, Fu Zhonghua, Guo Guanghua
Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, 330006, China.
J Orthop Surg Res. 2025 May 20;20(1):488. doi: 10.1186/s13018-025-05914-w.
This study investigated the role of ubiquitin C-terminal hydrolase L3 (UCHL3) in regulating endothelial cell (EC) pyroptosis and angiogenesis in diabetic foot ulcers (DFUs), with a focus on FOXM1 and NLRP3 inflammasomes.
Differentially expressed genes in DFUs were identified using the GSE134431 dataset and cross-referenced with vascular formation-related factors from GeneCard and deubiquitinases from the UbiNet 2.0 database. A rat DFU model was used to evaluate wound healing, with or without UCHL3 overexpression and FOXM1 knockdown. Histological analysis and immunohistochemistry were employed to assess tissue morphology and the expression of CD31, eNOS, UCHL3, and FOXM1. In vitro, high glucose-induced human umbilical vein ECs (HUVECs) were transfected with UCHL3 overexpression and FOXM1 knockdown constructs. Cell viability, migration, and angiogenesis were assessed.
UCHL3 expression was significantly reduced in DFU tissues. UCHL3 overexpression promoted wound healing in a rat model, while FOXM1 knockdown impaired wound healing and vascular formation. In HUVECs, UCHL3 overexpression enhanced cell viability, migration, and angiogenesis, accompanied by reduced NLRP3 and N-GSDMD levels. FOXM1 knockdown reversed these effects, but treatment with the NLRP3 inhibitor, MCC950, alleviated this damage.
UCHL3 enhances FOXM1 deubiquitination, inhibits NLRP3 inflammasome activation, and reduces EC pyroptosis, thereby contributing to DFU healing. UCHL3 and FOXM1 are potential therapeutic targets for DFU.
本研究探讨了泛素C末端水解酶L3（UCHL3）在调节糖尿病足溃疡（DFU）中内皮细胞（EC）焦亡和血管生成中的作用，重点关注FOXM1和NLRP3炎性小体。
使用GSE134431数据集鉴定DFU中差异表达的基因，并与来自GeneCard的血管形成相关因子和来自UbiNet 2.0数据库的去泛素酶进行交叉引用。使用大鼠DFU模型评估伤口愈合情况，分别进行UCHL3过表达和FOXM1敲低。采用组织学分析和免疫组织化学评估组织形态以及CD31、eNOS、UCHL3和FOXM1的表达。在体外，用UCHL3过表达和FOXM1敲低构建体转染高糖诱导的人脐静脉内皮细胞（HUVECs）。评估细胞活力、迁移和血管生成。
DFU组织中UCHL3表达显著降低。UCHL3过表达促进大鼠模型中的伤口愈合，而FOXM1敲低则损害伤口愈合和血管形成。在HUVECs中，UCHL3过表达增强细胞活力、迁移和血管生成，同时NLRP3和N-GSDMD水平降低。FOXM1敲低逆转了这些作用，但用NLRP3抑制剂MCC950处理可减轻这种损伤。
UCHL3增强FOXM1去泛素化，抑制NLRP3炎性小体激活，减少EC焦亡，从而促进DFU愈合。UCHL3和FOXM1是DFU的潜在治疗靶点。
