NEXN protects against vascular calcification by promoting SERCA2 SUMOy-lation and stabilization

Vascular calcification, a key risk factor for cardiovascular diseases, is driven by the phenotypic transition of vascular smooth muscle cells (VSMCs) 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 were used to explore the cell-specific roles and molecular mechanisms of NEXN in vascular calcification. VSMC-specific NEXN knockout exacerbated calcification, while NEXN overexpression alleviated it. NEXN was shown to interact with SERCA2, enhancing its SUMOylation, stability, and function, thereby protecting against calcification. These findings suggest that NEXN modulates vascular calcification through SERCA2 stabilization, offering potential therapeutic strategies by targeting NEXN-SERCA2 interactions or enhancing SERCA2 SUMOylation to prevent vascular calcification and its complications.