OTUD1 delays wound healing by regulating endothelial function and angiogenesis in diabetic mice
- J Adv Res. 2025 Apr 27:S2090-1232(25)00282-6. doi: 10.1016/j.jare.2025.04.038.
- 1. Zhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea.
- 2. Zhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, China.
- 3. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea.
- 4. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
- 5. Zhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: [email protected].
- 6. Zhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, China. Electronic address: [email protected].
- 7. Zhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, China. Electronic address: [email protected].
Introduction: Diabetic non-healing wounds represent a major complication of diabetes, primarily due to impaired angiogenesis. Ovarian tumor Deubiquitinase 1 (OTUD1), a Deubiquitinase, has been implicated in vascular pathophysiology; however, its role in endothelial dysfunction and angiogenesis during diabetic wound healing is still poorly understood.
Objectives: This study explores whether OTUD1 influences angiogenesis and its underlying mechanisms.
Methods: We developed OTUD1 knockout mice and induced type 1 and type 2 diabetes mellitus (T1DM and T2DM) by administering streptozotocin (STZ) alone or in combination with a high-fat diet (HFD), respectively. Human umbilical vein endothelial cells (HUVECs) incubated with high glucose and palmitic acid (HG + PA) were utilized to imitate hyperglycemia-induced endothelial dysfunction in vitro. Mass spectrometry combined with immunoprecipitation analysis was used to analyze the interacting proteins of OTUD1. Moreover, we developed endothelial-specific OTUD1 knockdown db/db mice using an adeno-associated virus serotype 2/BI30 (AAV2/BI30) vector.
Results: Increased OTUD1 expressions were observed both in diabetic wound tissues and in HUVECs treated with HG + PA. OTUD1 deficiency promoted angiogenesis and fibrosis in wound tissues of T1DM and T2DM mice and alleviated HG + PA-induced endothelial migration inhibition, tube formation impairment, and oxidative stress in HUVECs. Mechanistically, OTUD1 directly interacted with β-catenin, reducing its K63-linked ubiquitination at residues K496, K508, and K625 via its catalytic site C320. This modification facilitated β-catenin phosphorylation, restricted its nuclear translocation, and downregulated the expression of angiogenesis-related factors. Finally, pharmacological inhibition of β-catenin reversed the improvement of delayed wound healing induced by OTUD1 knockdown in db/db mice.
Conclusion: These findings elucidate the OTUD1-β-catenin pathway's role in endothelial dysfunction-associated angiogenesis and suggest OTUD1 as a promising therapeutic target for diabetic non-healing wounds.