In summary, our study indicated that Piezo1 activation aggravates endothelial oxidative stress injury and the inflammatory response in a high-glucose environment, suggesting a novel way for Piezo1 to regulate endothelial function by participation in oxidative stress during hyperglycemia, which proposed a novel approach for alleviating endothelial cell damage induced by high glucose. Here, PIEZO1 is linked to Hyperglycemia.