Mechanistic and Phytochemical Basis of Shexiang Xintongning Against Atherosclerosis: Insights from Network Pharmacology and Molecular Docking

Introduction: Shexiang Xintongning (SXN) is a Chinese medicinal compound used to treat cardiovascular diseases and has been formulated into a commercial tablet. Based on Traditional Chinese Medicine (TCM) theory, SXN has anti-atherosclerotic effects. Despite its clinical application, the mechanism of action of SXN remains poorly understood. This research seeks to clarify the molecular pathways and active constituents through which SXN combats atherosclerosis. Methods: In this study, network pharmacology was used to predict potential targets and biological processes involved in SXN’s treatment of atherosclerosis (AS). AS was induced in ApoE⁻/⁻ mice by feeding them a high-fat diet (HFD). The anti-atherosclerosis effects of SXN were observed in the aorta, aortic root, and serum. Based on the screening pathways and targets, experimental analyses were conducted to elucidate the mechanisms underlying its pharmacological action. Results: The chemical constituents of SXN were identified using UPLC/MS-MS analysis. The main components, including Muscone, Jasmone, Tetramethylpyrazine, Ferulic acid, trans-Cinnamic acid, and Senkyunolide H, were identified. Network pharmacology analysis revealed that the antiatherosclerotic effects of SXN were closely associated with the HIF-1 signaling pathway and the key factor HIF-1α. SXN significantly reduced atherosclerotic plaque formation, improved lipid profiles, suppressed inflammation, and alleviated oxidative stress in a dose-dependent manner. Mechanistically, SXN downregulated HIF-1α/HIF-2α while upregulating GPX4 and SLC7A11, indicating inhibition of ferroptosis. Discussion: These findings suggest that SXN exerts anti-atherosclerotic effects mainly by modulating the HIF-1 signaling pathway, improving lipid metabolism, attenuating inflammation and oxidative stress, and inhibiting ferroptosis, thereby providing mechanistic support for its traditional use in cardiovascular disease. Conclusion: SXN demonstrates significant anti-atherosclerotic efficacy by targeting the HIF- 1α/SLC7A11/GPX4 signaling axis, thereby elucidating novel mechanistic paradigms underlying cardiovascular therapeutic applications of Traditional Chinese Medicine and establishing ferroptosis as a critical molecular target for atherosclerotic disease intervention.