2. Academic Validation
  3. NEXN protects against vascular calcification by promoting SERCA2 SUMOylation and stabilization

NEXN protects against vascular calcification by promoting SERCA2 SUMOylation and stabilization

  • Nat Commun. 2025 Aug 29;16(1):8074. doi: 10.1038/s41467-025-63462-7.
Wenjie Guo # 1 2,  Wenjing Guo # 1 2,  Boliang Chen # 1 2,  Zexuan Lin 1 2,  Zhuohua Wen 3,  Jiamin Ye 1 2,  Wei Feng 4,  Xin Feng 3,  Jianyun Yan 1 2,  Pingzhen Yang 1 2,  Kunfu Ouyang 5,  Yifei Li 6,  Hanyan Yang 7 8,  Caiwen Ou 9,  Canzhao Liu 10 11
Affiliations

Affiliations

  • 1 Department of Cardiology, Laboratory of Heart Center, Heart Center, Center for Translational Medicine Research, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
  • 2 Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, China.
  • 3 Neurosurgery Center, Department of Cerebrovascular Surgery, Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
  • 4 Department of Medicine, University of California San Diego, La Jolla, CA, USA.
  • 5 Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China.
  • 6 Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital Sichuan University Chengdu, Sichuan, China.
  • 7 Department of Cardiology, Laboratory of Heart Center, Heart Center, Center for Translational Medicine Research, Zhujiang Hospital, Southern Medical University, Guangzhou, China. hanyanyang58@163.com.
  • 8 Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, China. hanyanyang58@163.com.
  • 9 The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Southern Medical University, Dongguan, China. oucaiwen@smu.edu.cn.
  • 10 Department of Cardiology, Laboratory of Heart Center, Heart Center, Center for Translational Medicine Research, Zhujiang Hospital, Southern Medical University, Guangzhou, China. liucanzhao@smu.edu.cn.
  • 11 Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, China. liucanzhao@smu.edu.cn.
  • # Contributed equally.
PMID: 40883305 DOI: 10.1038/s41467-025-63462-7
Abstract

Vascular calcification, a key risk factor for cardiovascular diseases, is driven by the phenotypic transition of vascular smooth muscle cells from a contractile to an osteogenic phenotype. NEXN, a protein highly associated with heart function, has also been implicated as a potential susceptibility factor in the development of coronary artery disease, but its role in the progression of vascular calcification remains unclear. In this study, multi-transcriptomics analysis and various animal models of male mice were used to explore the cell-specific roles and molecular mechanisms of NEXN in vascular calcification. Here, we show that vascular smooth muscle cell-specific NEXN knockout exacerbates calcification, while NEXN overexpression alleviates it. Mechanistically, NEXN interacts with SERCA2, enhancing its SUMOylation, stability, and function, thereby protecting against calcification. These findings suggest potential therapeutic strategies by targeting NEXN-SERCA2 interactions or enhancing SERCA2 SUMOylation to prevent vascular calcification and its complications.

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