Abstract
Vascular calcification represents a convergent pathological feature of diverse cardiovascular diseases, yet the upstream molecular programs orchestrating this process remain poorly defined. Here, we uncover fibronectin type III domain-containing 1 (FNDC1) as a previously unrecognized regulator of vascular calcification across both microvascular and macrovascular beds. Integrative transcriptomic profiling of human calciphylaxis lesions and atherosclerotic coronaries identified FNDC1 as one of the most significantly upregulated genes. In primary human vascular smooth muscle cells, FNDC1 drove osteogenic phenotype switch and vascular calcification through activation of PI3K/AKT signaling and metabolic reprogramming. Mechanistically, FNDC1 directly binds to nicotinamide phosphoribosyltransferase (NAMPT) resulting in elevated intracellular NAD⁺ levels, thus coupling vascular signaling to control of NAD⁺ biosynthesis. In murine models, genetic deletion of Fndc1 or pharmacologic inhibition of NAMPT suppressed arterial calcification and prolonged survival. Clinically, circulating FNDC1 levels were elevated in patients with both calciphylaxis and coronary artery disease and independently predicted cardiovascular risk in 42,687 UK Biobank participants. Together, these findings establish FNDC1 as a central mediator of vascular pathology and highlight the FNDC1- NAMPT-NAD (+) axis as a promising target for therapeutic intervention.