Coronary artery disease (CAD), a critical condition resulting from systemic inflammation, metabolic dysfunction, and gut microbiota dysbiosis, poses a global public health challenge. ALW-II-41-27, a specific inhibitor of the EphA2 receptor, has shown anti-inflammatory prosperities. However, the impact of ALW-II-41-27 on atherosclerosis has not been elucidated. This study aimed to examine the roles of pharmacologically inhibiting EphA2 and the underlying mechanism in ameliorating atherosclerosis. ALW-II-41-27 was administered to apoE^−/− mice fed a high-fat diet via intraperitoneal injection. We first discovered that ALW-II-41-27 led to a significant reduction in atherosclerotic plaques, evidenced by reduced lipid and macrophage accumulation, alongside an increase in collagen and smooth muscle cell content. ALW-II-41-27 also significantly lowered plasma and hepatic cholesterol levels, as well as the colonic inflammation. Furthermore, gut microbiota was analyzed by metagenomics and plasma metabolites by untargeted metabolomics. ALW-II-41-27-treated mice enriched Enterococcus, Akkermansia, Eggerthella and Lactobaccilus, accompanied by enhanced secondary bile acids production. To explore the causal link between ALW-II-41-27-associated gut microbiota and atherosclerosis, fecal microbiota transplantation was employed. Mice that received ALW-II-41-27-treated mouse feces exhibited the attenuated atherosclerotic plaque. In clinical, lower plasma DCA and HDCA levels were determined in CAD patients using quantitative metabolomics and exhibited a negative correlation with higher monocytes EphA2 expression. Our findings underscore the potential of ALW-II-41-27 as a novel therapeutic agent for atherosclerosis, highlighting its capacity to modulate gut microbiota composition and bile acid metabolism, thereby offering a promising avenue for CAD.

冠状动脉疾病 （CAD） 是由全身炎症、代谢功能障碍和肠道微生物群失调引起的危急疾病，构成了全球公共卫生挑战。ALW-II-41-27 是 EphA2 受体的特异性抑制剂，已显示出抗炎作用。然而，ALW-II-41-27 对动脉粥样硬化的影响尚未阐明。本研究旨在探讨药理学抑制 EphA2 的作用以及改善动脉粥样硬化的潜在机制。ALW-II-41-27 被给予通过腹膜内注射喂食高脂肪饮食的 apoE^-/-小鼠。我们首先发现 ALW-II-41-27 导致动脉粥样硬化斑块的显着减少，脂质和巨噬细胞积累减少，同时胶原蛋白和平滑肌细胞含量增加。ALW-II-41-27 还显着降低血浆和肝脏胆固醇水平，以及结肠炎症。此外，通过宏基因组学分析肠道菌群，通过非靶向代谢组学分析血浆代谢物。ALW-II-41-27 处理的小鼠富含肠球菌、Akkermansia、Eggerthella 和 Lactobaccilus，伴有增强的次级胆汁酸产生。为了探讨 ALW-II-41-27 相关肠道菌群与动脉粥样硬化之间的因果关系，采用了粪便微生物群移植。接受 ALW-II-41-27 处理的小鼠粪便的小鼠表现出减弱的动脉粥样硬化斑块。在临床上，使用定量代谢组学测定 CAD 患者血浆 DCA 和 HDCA 水平较低，并与较高的单核细胞 EphA2 表达呈负相关。 我们的研究结果强调了 ALW-II-41-27 作为动脉粥样硬化新型治疗剂的潜力，突出了其调节肠道菌群组成和胆汁酸代谢的能力，从而为 CAD 提供了一条有前途的途径。