Shiwei Wendan Decoction alleviates atherosclerosis by suppressing endothelial inflammatory responses through the CHIP/ICAM1 axis

Backgroud Atherosclerosis is a chronic inflammatory vascular disease characterized by endothelial dysfunction, lipid deposition, and persistent vascular inflammation. Shiwei Wendan Decoction (SWWD), a classical traditional Chinese medicine formula used for cardiovascular disorders, has shown anti-atherosclerotic potential; however, its pharmacological mechanisms remain incompletely understood. Objective This study aimed to investigate the protective effects of SWWD against atherosclerosis and the underlying molecular mechanisms. Methods The chemical composition of SWWD was characterized by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Anti-atherosclerotic effects and molecular mechanisms were evaluated in AAV-PCSK9-induced and ApoE^−/− mouse models using integrated histological, multi-omics, and functional analyses. Mechanistic studies were further performed to investigate the involvement of salvianolic acid B (Sal B) and the CHIP/ICAM1 axis in endothelial inflammation. UPLC-MS profiling identified phenolic acids and flavonoids as major constituents of SWWD. Results SWWD reduced atherosclerotic lesion burden and lipid accumulation in both mouse models, with histological changes consistent with greater plaque stability. Treatment also reduced macrophage accumulation and ICAM1, VCAM1, and NOX2 protein levels, while DHE fluorescence tended to decrease. Integrated transcriptomic and proteomic analyses highlighted ubiquitination-related processes. SWWD increased CHIP protein abundance, and experiments with Sal B showed enhanced CHIP stability together with reduced ICAM1 expression and endothelial inflammatory activation. CHIP knockdown attenuated the protective effects of Sal B in human umbilical vein endothelial cells. These findings support a contribution of CHIP-associated regulation of ICAM1 to the endothelial effects of Sal B and suggest that this mechanism may account for part of the anti-atherosclerotic activity of SWWD. Conclusion These findings provide mechanistic insight into the anti-atherosclerotic effects of SWWD and support ubiquitin-associated endothelial inflammatory regulation as a potential therapeutic strategy for atherosclerosis.