Protective Mechanism of Aqueous Extract From Ixeris sonchifolia in Myocardial Ischemia–Reperfusion Injury: Insights From Network Pharmacology and Experimental Validation

ABSTRACT Ixeris sonchifolia (Bge.) Hance, commonly known as kudiezi (KDZ), has a bitter taste, acrid nature, and is cold in property. It is used for treating pain, heat, and detoxification, and additionally serves as both food and fodder. Previous pharmacological studies indicate cardiovascular protective effects of KDZ. However, its efficacy against myocardial ischemia–reperfusion injury (MI/RI) remains insufficiently studied. Mice were pretreated with KDZ aqueous extract via oral gavage for three consecutive days. On the fourth day, a myocardial ischemia/reperfusion (40 min/60 min) model was surgically induced. Echocardiography data showed significant improvements in left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) in the KDZ‐treated group. TTC staining showed that KDZ treatment significantly reduced the infarct size compared with the model group. These findings confirmed that KDZ aqueous extract mitigated injury and preserved cardiac function. Ultra high performance liquid chromatography‐mass spectrometry (UHPLC–MS) analysis identified 86 chemical components. Network revealed ten hub targets—including AKR1B1, CA2, XDH, ADORA1, ACHE, EGFR, TNF, IL‐2, RPS6KA3, NOX4—that are critically involved in oxidative stress and inflammatory pathways. Based on KEGG enrichment analysis, the screened genes showed significant enrichment in the AGE‐RAGE signaling pathway. Experimental results confirmed that the KDZ aqueous extract reduced serum AGEs levels and inhibited the expression of the oxidative regulatory proteins gp91‐phox and p47‐phox, as well as that of RAGE. This study demonstrated the KDZ aqueous extract attenuated MI/RI by targeting the AGE‐RAGE‐NOX axis.