USP25 ameliorates vascular remodeling by deubiquitinating FOXO3 and promoting autophagic degradation of FOXO3.

Yanghao CHEN; Bozhi YE; Diyun XU; Wante LIN; Zimin FANG; Xuefeng QU; Xue HAN; Wu LUO; Chen CHEN; Weijian HUANG; Hao ZHOU; Gaojun WU; Yi WANG; Guang LIANG

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USP25 ameliorates vascular remodeling by deubiquitinating FOXO3 and promoting autophagic degradation of FOXO3.

Author: Yanghao CHEN ¹ ; Bozhi YE ¹ ; Diyun XU ¹ ; Wante LIN ¹ ; Zimin FANG ¹ ; Xuefeng QU ² ; Xue HAN ² ; Wu LUO ³ ; Chen CHEN ¹ ; Weijian HUANG ¹ ; Hao ZHOU ¹ ; Gaojun WU ¹ ; Yi WANG ³ ; Guang LIANG ¹
Author Information

1. Department of Cardiology and the Key Laboratory of Cardiovascular Disease of Wenzhou, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, China.
2. School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou 310059, China.
3. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Publication Type:Journal Article
Keywords: Angiotensin II; Autolysosome; Deubiquitinase; Endothelial-to-mesenchymal transition; FOXO3; LC3B; USP25; Vascular remodeling
From: Acta Pharmaceutica Sinica B 2025;15(3):1643-1658
CountryChina
Language:English
Abstract: Long-term hypertension causes excessive vascular remodeling and leads to adverse cardiovascular events. Balance of ubiquitination and deubiquitination has been linked to several chronic conditions, including pathological vascular remodeling. In this study, we discovered that the expression of ubiquitin-specific protease 25 (USP25) is significantly up-regulated in angiotensin II (Ang II)-challenged mouse aorta. Knockout of Usp25 augments Ang II-induced vascular injury such as fibrosis and endothelial to mesenchymal transition (EndMT). Mechanistically, we found that USP25 interacts directly with Forkhead box O3 (FOXO3) and removes the K63-linked ubiquitin chain on the K258 site of FOXO3. We also showed that this USP25-mediated deubiquitination of FOXO3 increases its binding to light chain 3 beta isoform and autophagosomic-lysosomal degradation of FOXO3. In addition, we further validated the biological function of USP25 by overexpressing USP25 in the mouse aorta with AAV9 vectors. Our studies identified FOXO3 as a new substrate of USP25 and showed that USP25 may be a potential therapeutic target for excessive vascular remodeling-associated diseases.