Exploring the mechanism by which UCHL3 alleviates diabetic foot ulcers: FOXM1/NLRP3 inflammasome-mediated angiogenesis and endothelial cell pyroptosis
Abstract Background 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. Methods Differentially expressed genes in DFUs were identif...
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BMC
2025-05-01
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| Series: | Journal of Orthopaedic Surgery and Research |
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| Online Access: | https://doi.org/10.1186/s13018-025-05914-w |
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| author | Xincheng Liao Zhengying Jiang Zhonghua Fu Guanghua Guo |
| author_facet | Xincheng Liao Zhengying Jiang Zhonghua Fu Guanghua Guo |
| author_sort | Xincheng Liao |
| collection | DOAJ |
| description | Abstract Background 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. Methods 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. Results 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. Conclusion 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. |
| format | Article |
| id | doaj-art-c8a02e39a6b847569b88ad35129bd62b |
| institution | OA Journals |
| issn | 1749-799X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| series | Journal of Orthopaedic Surgery and Research |
| spelling | doaj-art-c8a02e39a6b847569b88ad35129bd62b2025-08-20T01:53:25ZengBMCJournal of Orthopaedic Surgery and Research1749-799X2025-05-0120111410.1186/s13018-025-05914-wExploring the mechanism by which UCHL3 alleviates diabetic foot ulcers: FOXM1/NLRP3 inflammasome-mediated angiogenesis and endothelial cell pyroptosisXincheng Liao0Zhengying Jiang1Zhonghua Fu2Guanghua Guo3Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityMedical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityMedical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityMedical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityAbstract Background 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. Methods 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. Results 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. Conclusion 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.https://doi.org/10.1186/s13018-025-05914-wDiabetic foot ulcersUCHL3FOXM1NLRP3 inflammasomeEndothelial cells |
| spellingShingle | Xincheng Liao Zhengying Jiang Zhonghua Fu Guanghua Guo Exploring the mechanism by which UCHL3 alleviates diabetic foot ulcers: FOXM1/NLRP3 inflammasome-mediated angiogenesis and endothelial cell pyroptosis Journal of Orthopaedic Surgery and Research Diabetic foot ulcers UCHL3 FOXM1 NLRP3 inflammasome Endothelial cells |
| title | Exploring the mechanism by which UCHL3 alleviates diabetic foot ulcers: FOXM1/NLRP3 inflammasome-mediated angiogenesis and endothelial cell pyroptosis |
| title_full | Exploring the mechanism by which UCHL3 alleviates diabetic foot ulcers: FOXM1/NLRP3 inflammasome-mediated angiogenesis and endothelial cell pyroptosis |
| title_fullStr | Exploring the mechanism by which UCHL3 alleviates diabetic foot ulcers: FOXM1/NLRP3 inflammasome-mediated angiogenesis and endothelial cell pyroptosis |
| title_full_unstemmed | Exploring the mechanism by which UCHL3 alleviates diabetic foot ulcers: FOXM1/NLRP3 inflammasome-mediated angiogenesis and endothelial cell pyroptosis |
| title_short | Exploring the mechanism by which UCHL3 alleviates diabetic foot ulcers: FOXM1/NLRP3 inflammasome-mediated angiogenesis and endothelial cell pyroptosis |
| title_sort | exploring the mechanism by which uchl3 alleviates diabetic foot ulcers foxm1 nlrp3 inflammasome mediated angiogenesis and endothelial cell pyroptosis |
| topic | Diabetic foot ulcers UCHL3 FOXM1 NLRP3 inflammasome Endothelial cells |
| url | https://doi.org/10.1186/s13018-025-05914-w |
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