Atherosclerosis is a cardiovascular disease, accounting for the most common mortality cause worldwide. Notoginsenoside R1 (NGR1) is a characteristic saponin of Radix notoginseng that exhibits anti-inflammatory and antioxidant effects while modulating lipid metabolism. Evidence suggests that NGR1 exerts cardioprotective, neuroprotective, and anti-atherosclerosis effects. However, underlying NGR1 mechanisms alleviating atherosclerosis (AS) have not been examined. This study used a network pharmacology approach to construct the drug-target-disease correlation and protein–protein interaction (PPI) network of NGR1 and AS. Moreover, functional annotation and pathway enrichment analyses deciphered the critical biological processes and signaling pathways potentially regulated by NGR1. The protective effect of NGR1 against AS and the underlying mechanism(s) was assessed in an atherogenic apolipoprotein E-deficient (ApoE^−/−) mice in vivo and an oxidized low-density lipoprotein (ox-LDL)-induced macrophage model in vitro. The network pharmacology and molecular docking analyses revealed that NGR1 protects against AS by targeting the NLRP3/caspase-1/IL-1β pathway. NGR1 reduced foam cell formation in ox-LDL-induced macrophages and decreased atherosclerotic lesion formation, serum lipid metabolism, and inflammatory cytokines in AS mice in vivo. Therefore, NGR1 downregulates the NLRP3 inflammasome complex gene expression of NLRP3, caspase-1, ASC, IL-1β, and IL-18, in vivo and in vitro.

动脉粥样硬化是一种心血管疾病，是全世界最常见的死亡原因。三七皂苷 R1 (NGR1) 是三七的特征性皂苷，在调节脂质代谢的同时具有抗炎和抗氧化作用。有证据表明 NGR1 具有心脏保护、神经保护和抗动脉粥样硬化作用。然而，NGR1 缓解动脉粥样硬化 (AS) 的潜在机制尚未得到研究。本研究采用网络药理学方法构建了NGR1和AS的药物-靶标-疾病相关性和蛋白质-蛋白质相互作用（PPI）网络。此外，功能注释和通路富集分析破译了 NGR1 可能调控的关键生物过程和信号通路。在致动脉粥样硬化载脂蛋白 E 缺陷 (ApoE ^−/− ) 小鼠体内和氧化低密度脂蛋白 (ox-LDL) 诱导的体外巨噬细胞模型中评估了 NGR1 对 AS 的保护作用及其潜在机制。网络药理学和分子对接分析表明，NGR1 通过靶向 NLRP3/caspase-1/IL-1β 通路来预防 AS。NGR1 减少了 ox-LDL 诱导的巨噬细胞中泡沫细胞的形成，并减少了 AS 小鼠体内动脉粥样硬化病变的形成、血清脂质代谢和炎症细胞因子。因此，在体内和体外，NGR1 下调 NLRP3、caspase-1、ASC、IL-1β 和 IL-18 的 NLRP3 炎性体复合体基因表达。