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Arterial calcification is the principal pathological marker of diabetic vascular complications. The principal causes of arterial calcification include hyperglycemia, advanced glycation end products (AGEs), and increased mechanical stress. Piezo1 is a mechanosensitive channel that is critically involved in vascular disease. The aim of this study is to clarify how Piezo1 activation promotes the calcification of cardiac smooth muscle cells through calcium-regulating mechanisms. In this study, the calcium-dependent regulatory mechanism of Piezo1 in a diabetic vascular calcification cell model was examined by using pharmacological and genetic approaches. Vascular smooth muscle-specific Piezo1 knockout mice were used to evaluate the protective function of Piezo1 in diabetic vascular calcification. In the diabetic mouse model, vascular calcification was associated with increased Piezo1 expression and enhanced O-GlcNAcylation. Piezo1 activation exacerbated calcification and O-GlcNAcylation in human coronary smooth muscle cells (HCASMCs), whereas Piezo1 inhibition alleviated these changes. Subsequent mechanistic studies revealed that Piezo1 interacts with Yes-associated protein 1 (YAP) and O-linked N-acetylglucosamine transferase (OGT) through calcium-dependent mechanisms, thereby enhancing the O-GlcNAcylation of runt-related transcription factor 2 (RUNX2) and promoting osteogenic development. Targeted Piezo1 ablation in smooth muscle reduced diabetes-related vascular calcification, increased vascular compliance, and restored regular molecular expression. This study demonstrated that Piezo1 augments OGT activity via a calcium-dependent YAP activation pathway, promoting the O-GlcNAcylation of Runx2, thereby advancing the osteogenic differentiation of HCASMCs and ultimately aggravating diabetic vascular calcification. Inhibiting the Piezo1 signaling pathway offers a novel approach for mitigating diabetic vascular complications.