A functional drug discovery in ameliorating cardiac remodeling based on NRF2-regulated oxidative stress

Abstract Food and medicine homologous (FMH) products provide enhanced safety and tolerability. This study aimed to identify functional FMH compounds against cardiac hypertrophy. Bioinformatics analysis and in vivo experiments were utilized to pinpoint key genes in cardiac remodeling. A functional component screening was performed using the FMH compound database (FMHCD), followed by an evaluation of drug-like properities. Pharmacological assessments included measures of cardiac function, cardiac hypertrophy and fibrosis determination, and mitochondrial function. Transcriptome analysis was carried out to explore potential mechanisms. Interaction studies involved luciferase reporter assays, chromatin immunoprecipitation (ChIP) assays, and loss-of- and gain-of-function verifications. NRF2 has been identified as a critical gene in cardiac remodeling. Among the FMHCD compounds, β-ecdysterone (β-Ecd) was the most promising NRF2 enhancer, showing dose-dependent effectiveness in reversing cardiac remodeling. High concentration of β-Ecd resulted in approximately a 2.15-fold improvement. Downregulation of NRF2 negated the beneficial effects of β-Ecd, increasing cardiac hypertrophy by roughly 2.14-fold, oxidative stress by 1.94-fold, and mitochondrial dysfunction by 1.69- to 2.14-fold. Slc41a3 was identified and confirmed as being directly regulated by NRF2. Under AngII stimulation, knockdown of Slc41a3 in cardiomyocytes reduced mitochondrial oxidative stress by 87.9% and mitochondrial dysfunction by 1.8-fold. Overexpression of Slc41a3 counteracted the protective effects of β-Ecd, elevating mitochondrial oxidative stress by approximately 1.75-fold and impairing mitochondrial function by 1.75- to 2.93-fold in cardiomyocytes. β-Ecd alleviates cardiac hypertrophy via the NRF2/Slc41a3 pathway, regulating oxidative stress and mitochondrial dysfunction.