Glabridin improves cardiac remodeling after myocardial infarction by activating PPARγ to regulate the ubiquitination and degradation of EGFR

Acute myocardial infarction leads to myocardial inflammation and necroptosis, and is a major cause of heart failure, cardiovascular dysfunction, and mortality. Adverse remodeling and myocardial fibrosis following myocardial infarction are key pathophysiological processes contributing to poor prognosis. Licorice, a widely utilized herb and food, contains glabridin, a bioactive component that acts as a potent PPARγ agonist. Glabridin has demonstrated multiple beneficial biological effects, including antioxidative stress, anti-inflammation, anti-atherosclerosis, and tumor progression inhibition. However, its role in cardiovascular diseases remains understudied. Using C57BL/6 mice, a myocardial infarction model was established via left coronary artery ligation. Mice were treated with glabridin by oral gavage daily for 4 consecutive weeks post-surgery. Cardiac function and various indicators were assessed to evaluate the therapeutic effects. Additionally, primary cardiac fibroblasts were isolated from the mice for in vitro experiments to verify the effects of glabridin and further explore its mechanism of action. Glabridin treatment significantly improved cardiac fibrosis and alleviated cardiac dysfunction in mice. Mechanistically, glabridin activates PPARγ, thereby promoting the ubiquitination and degradation of EGFR, inhibiting the activation of the downstream PI3K/Akt signaling pathway, and mitigating myocardial fibrosis progression. Glabridin links the PI3K/Akt pathway and promote EGFR ubiquitination, offering insights into myocardial fibrosis mechanisms and potential therapeutic targets.