Cardioprotective Effect of Licorice Extract Against Myocardial Ischemia and Ischemia/Reperfusion Injury via Blocking Cardiac Inflammation by Sirt3/ NLRP3

ABSTRACT Cardioprotective formulations in traditional Chinese medicine often combine cold and hot herbs, with licorice frequently included to balance their properties and reduce adverse effects. However, the independent cardioprotective mechanisms of licorice in ischemic heart disease remain unclear. This study aimed to investigate the effects of licorice extract (GC) on myocardial ischemia (MI) and ischemia/reperfusion (MI/R) injury. Myocardial injury models were established using H 2 O 2 ‐induced H9c2 cardiomyocytes and left anterior descending coronary artery ligation in rats. Cardioprotective effects were evaluated through electrocardiography, echocardiography, and pharmacodynamic assessments. Network pharmacology and PCR were used to explore the anti‐inflammatory mechanism, followed by investigation of the upstream inflammatory pathways using Western blotting, co‐immunoprecipitation, immunofluorescence, and molecular docking. Metabolomics confirmed GC's impact on terminal metabolic disturbances. Pharmacodynamic evaluations demonstrated that GC exerted significant cardioprotective effects both in vitro and in vivo. Network pharmacology suggested anti‐inflammatory potential, which was confirmed by PCR showing reduced levels of IL‐1β, IL‐6, and TNF‐α. Expression analysis of seven Sirtuin and four NOD‐like receptor family members revealed that GC's anti‐inflammatory effect was mediated by upregulation of Sirt3, leading to inhibition of NLRP3 inflammasome activation, decreased Caspase‐1 activity, and reduced secretion of IL‐1β and IL‐18. Additionally, GC modulated ischemia‐induced metabolic disturbances, notably restoring disrupted amino acid and unsaturated fatty acid metabolism. In conclusion, GC exerted cardioprotective effects by suppressing inflammation through the Sirt3/NLRP3 axis and restoring metabolic homeostasis. These findings supported its traditional use and suggested its potential application in cardiovascular health.