NEXN protects against vascular calcification by promoting SERCA2 SUMOylation and stabilization

Wenjie Guo, Wenjing Guo, Boliang Chen, Zexuan Lin, Zhuohua Wen, Jiamin Ye, Wei Feng, Xin Feng, Jianyun Yan, Pingzhen Yang, Kunfu Ouyang, Yifei Li, Hanyan Yang (), Caiwen Ou () and Canzhao Liu ()
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Wenjie Guo: Southern Medical University
Wenjing Guo: Southern Medical University
Boliang Chen: Southern Medical University
Zexuan Lin: Southern Medical University
Zhuohua Wen: Southern Medical University
Jiamin Ye: Southern Medical University
Wei Feng: University of California San Diego
Xin Feng: Southern Medical University
Jianyun Yan: Southern Medical University
Pingzhen Yang: Southern Medical University
Kunfu Ouyang: Peking University Shenzhen Hospital
Yifei Li: West China Second University Hospital Sichuan University Chengdu
Hanyan Yang: Southern Medical University
Caiwen Ou: Southern Medical University
Canzhao Liu: Southern Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63462-7

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