TY  - JOUR
AU  - Xiao, Dan
AU  - Li, Runze
AU  - Lin, Xuantong
AU  - Jin, Haifeng
AU  - Lu, Weihong
AU  - Li, Hui
AU  - Lin, Yan
PY  - 2025
TI  - A functional drug discovery in ameliorating cardiac remodeling based on NRF2-regulated oxidative stress
JO  - Food Science and Human Wellness
SN  - 2097-0765
AB  - Background: Medicine and food homologous (MFH) products provide enhanced safety and tolerability. This study aimed to identify functional MFH compounds against cardiac hypertrophy. Methods: Bioinformatics analysis and in vivo experiments were utilized to pinpoint key genes in cardiac remodeling. A functional component screening was performed using the Medical Homology Compound Database (MHCD), 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. Results: NRF2 has been identified as a critical gene in cardiac remodeling. Among the MHCD compounds, β-ecdysterone was the most promising NRF2 enhancer, showing dose-dependent effectiveness in reversing cardiac remodeling. High concentration of β-ecdysterone resulted in approximately a 2.15-fold improvement. Downregulation of NRF2 negated the beneficial effects of β-ecdysterone, 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-ecdysterone, elevating mitochondrial oxidative stress by approximately 1.75-fold and impairing mitochondrial function by 1.75- to 2.93-fold in cardiomyocytes. Conclusions: β-ecdysterone alleviates cardiac hypertrophy via the NRF2/Slc41a3 pathway, regulating oxidative stress and mitochondrial dysfunction.
UR  - https://doi.org/10.26599/FSHW.2025.9250500
DO  - 10.26599/FSHW.2025.9250500