In this study, we screened potential natural compounds for the treatment of myocardial infarction (MI) and explored the underlying mechanisms. We built three machine learning models to screen the potential compounds. qPCR, flow cytometry, immunohistochemistry, and immunofluorescence analyses were applied to analyze the pharmacological effects of the compounds on macrophages/monocytes in vivo and in vitro. Arctigenin (AG) was selected as a candidate, and echocardiography, Masson’s trichrome staining, and TUNEL staining were utilized to detect the effect of AG on MI in vivo. Transcriptome analysis and subsequent bioinformatics analyses were performed to predict the target of the selected compound. Western blot and luciferase reporter assays were used to confirm the target and mechanism of AG. The reversibility of the effects of AG were verified through overexpression of NFAT5. The results showed that AG can improve cardiac injury after MI by reducing infarct size, improving heart function, and inhibiting cardiac death. In addition, AG suppresses inflammatory macrophages/monocytes and proinflammatory cytokines in vivo and in vitro. Transcriptomic and biological experiments revealed that AG modulates macrophage polarization via the NFAT5-induced signaling pathway. Therefore, our data suggest that AG can improve MI by inhibiting the inflammatory phenotype of macrophages/monocytes through targeting of NFAT5.

在这项研究中，我们筛选了用于治疗心肌梗塞 (MI) 的潜在天然化合物并探索了潜在的机制。我们建立了三个机器学习模型来筛选潜在的化合物。应用 qPCR、流式细胞术、免疫组织化学和免疫荧光分析来分析化合物在体内和体外对巨噬细胞/单核细胞的药理作用。选择牛蒡甙元（AG）作为候选物，利用超声心动图、Masson 三色染色和 TUNEL 染色检测 AG 在体内对 MI 的影响。进行转录组分析和随后的生物信息学分析以预测所选化合物的靶标。蛋白质印迹和荧光素酶报告基因检测用于确认 AG 的靶点和机制。通过 NFAT5 的过表达验证了 AG 作用的可逆性。结果表明，AG 可以通过减少梗死面积、改善心脏功能和抑制心源性死亡来改善 MI 后的心脏损伤。此外，AG 在体内和体外抑制炎性巨噬细胞/单核细胞和促炎细胞因子。转录组学和生物学实验表明，AG 通过 NFAT5 诱导的信号通路调节巨噬细胞极化。因此，我们的数据表明 AG 可以通过靶向 NFAT5 抑制巨噬细胞/单核细胞的炎症表型来改善 MI。AG 在体内和体外抑制炎性巨噬细胞/单核细胞和促炎细胞因子。转录组学和生物学实验表明，AG 通过 NFAT5 诱导的信号通路调节巨噬细胞极化。因此，我们的数据表明 AG 可以通过靶向 NFAT5 抑制巨噬细胞/单核细胞的炎症表型来改善 MI。AG 在体内和体外抑制炎性巨噬细胞/单核细胞和促炎细胞因子。转录组学和生物学实验表明，AG 通过 NFAT5 诱导的信号通路调节巨噬细胞极化。因此，我们的数据表明 AG 可以通过靶向 NFAT5 抑制巨噬细胞/单核细胞的炎症表型来改善 MI。