Cardioprotective Role of 5,7,4′‐Trimethoxy Flavanone Through PI3K/AKT‐Nrf2 Signaling in Mice

ABSTRACT Myocardial hypertrophy represents a pathological cardiac adaptation involving abnormal cardiomyocyte enlargement that compromises ventricular function and precipitates heart failure. The flavonoid compound 5,7,4′‐trimethoxy flavanone exhibits significant anti‐inflammatory and antioxidant activities, highlighting its potential as a phytocompound with desired pharmacological value for managing hypertrophic cardiac conditions. This investigation examined the cardioprotective effects of 5,7,4′‐trimethoxy flavanone against isoproterenol‐induced myocardial hypertrophy in Swiss albino mouse models. Treatment with this flavonoid significantly reduced cardiac mass and myocyte diameter. As a result, expression levels of hypertrophic biomarkers such as ANP, BNP, calcineurin, and GATA4 in isoproterenol‐challenged animals were also markedly decreased. Additionally, 5,7,4′‐trimethoxy flavanone administration diminished expression of oxidative stress markers and inhibited myocardial fibrosis development, as confirmed through Masson's trichrome histological evaluation. This mechanistic investigation revealed that this compound downregulated PI3K/AKT signaling proteins while enhancing Nrf2‐mediated antioxidant pathways. These molecular effects resulted in inhibition of apoptosis and enhanced cellular survival, marked by elevated Bcl‐2 and Bcl‐xL expression, as well as reduced caspase‐3 enzymatic activity and decreased TUNEL‐positive cardiomyocytes. The experimental evidence supports the potential of 5,7,4′‐trimethoxy flavanone as an effective adjunct for cardiac hypertrophy through its dual modulation of PI3K/AKT and Nrf2 signaling networks. These findings establish 5,7,4′‐trimethoxy flavanone as a promising cardioprotective agent, warranting further clinical development for hypertrophic cardiomyopathy treatment strategies.