Eriodictyol targets the ubiquitination/phosphorylation of apoptosis signal-regulating kinase 1 and alleviates pressure-overload induced myocardial fibrosis in mice.

Background

AND

Purpose

Myocardial fibrosis, a critical pathogenic driver of cardiovascular events, is primarily characterized by extracellular matrix deposition and cardiac fibroblast proliferation and activation. Eriodictyol (ERIO) is an extractable natural compound widely found in fruits and vegetables, possessing positive antioxidant and anti-inflammatory benefits. This study primarily explores the role and molecular mechanism of ERIO in pressure overload-induced myocardial fibrosis. EXPERIMENTAL APPROACH We established an in vivo cardiac remodelling model using transverse aortic constriction (TAC) surgery and an in vitro myocardial fibrosis model induced by transforming growth factor β (TGF-β). For mechanistic exploration, we administered adeno-associated virus (AAV) carrying cardiac fibroblast-specific apoptosis signal-regulating kinase 1 (ASK1) overexpression via tail vein injection, generated a cardiac fibroblast-specific ASK1 knockout mouse model, and established an in vitro neonatal rat cardiac fibroblast (NRCF) model with co-intervention of the selective ASK1 inhibitor GS-4977. KEY

Results

ERIO significantly improved pressure overload-induced cardiac dysfunction and myocardial fibrosis. In addition, ERIO inhibited oxidative stress and inflammatory responses and improved mitochondrial function. Specifically, our mechanistic study revealed that ERIO binds to the K398 site of ASK1, regulating its ubiquitination and phosphorylation activation, down-regulating its downstream JNK/P38 signalling axis and inhibiting the proliferation and activation of cardiac fibroblasts.

Conclusions

AND IMPLICATIONS ERIO is a safe, effective natural flavonoid with promising preclinical efficacy, suggesting its potential clinical translation for myocardial fibrosis and offering new therapeutic targets to prevent heart failure progression.