Background <p>Vascular endothelial inflammation is a key pathological process underlying various inflammatory vascular conditions, which can lead to severe cardiovascular complications. Shexiang Tongxin Dropping Pills (STDP) is a traditional Chinese medicine formulation clinically used for cardiovascular disorders and has shown protective effects on the vascular endothelium. However, the specific mechanisms by which STDP attenuates vascular endothelial inflammation remain incompletely elucidated.</p> Methods <p>An experimental model of LCWE-induced vasculitis was established by intraperitoneal injection of lactobacillus casei cell wall extract (LCWE) in C57BL/6 mice. The effects of STDP were evaluated through whole blood analysis, EVG staining, and immunofluorescent staining for adhesion molecules (ICAM-1, VCAM-1) and macrophage infiltration. An in vitro endothelial damage model was established by stimulating murine vascular endothelial cells (MVECs) with LCWE. Network pharmacology, calcium imaging, and siRNA-mediated knockdown of Piezo1 were employed to elucidate the underlying mechanism.</p> Results <p>STDP greatly alleviated the weight loss and reduced spleen coefficient in LCWE-induced mice. It decreased the proportion of monocytes in the blood, reduced the area and maximum diameter of the abdominal aorta, and preserved the structural integrity of elastic fibers in the abdominal aorta wall as revealed by EVG staining. Besides, STDP significantly alleviated vascular endothelial inflammation both in the mouse model and in the cell model, as manifested by inhibition of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression. Mechanistically, STDP significantly inhibited Piezo1 channel activation, thereby reducing calcium ion (Ca²⁺) influx. This inhibitory effect prevented the activation of the NLRP3 inflammasome in endothelial cells, thus protecting endothelial cells and alleviating inflammation.</p> Conclusion <p>STDP attenuates vascular inflammation by downregulating Piezo1 expression, thereby reducing Ca²⁺ influx and suppressing NLRP3 inflammasome activation. The Piezo1/Ca²⁺/NLRP3 pathway may represent a novel therapeutic target for ameliorating vascular endothelial inflammation.</p>