β-ecdysterone, a functional component derived from medicine and food homologous herb Achyranthes bidentata, has shown potential in cardiovascular protection according to our previous studies. This study aims to further investigate its neuromodulatory mechanism in cardiac hypertrophy. The anti-hypertrophic effects of β-ecdysterone were validated both in vivo and in vitro. Transcriptomic analysis of cardiac and medullary tissues revealed the involvement of neuroregulatory pathways, including modulation of sympathetic acitivity. β-ecdysterone significantly reduced norepinephrine (NE) levels and its metabolites, which correlated with hypertrophic markers. Weighted Gene Co-Expression Network Analysis (WGCNA) identified Dhx37 as a key gene associated with cardiac hypertrophy. In a co-culture model of sympathetic neurons (PC-12) and cardiomyocytes (H9C2), β-ecdysterone suppressed NE secretion and calcium influx in PC-12 cells under Angiotensin II (AngII) stimulation, an effect abolished by .Dhx37 knockdown in cardiomyocytes. These findings suggest that β-ecdysterone alleviates cardiac hypertrophy by modulating cardiac-sympathetic neuron interaction via the Dhx37 pathway, offering a novel neurocardiac regulatory target for MFH-based therapies.

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.