As a hallmark of chronic kidney disease (CKD), arterial stiffening is related to increased vascular inflammation and cardiovascular morbidity, whereas the underlying mechanism is unclear. The study demonstrates that increased arterial stiffness precedes the onset of vascular inflammation, and matrix stiffness stimulates the transdifferentiation of vascular smooth muscle cells (VSMCs) to an inflammatory phenotype via activating Runx2-NLRP3 signaling, which provides novel insights into CKD-related cardiovascular disorder treatment.