Astragaloside II alleviates cardiac hypertrophy by targeting aminoacylase‐1: a novel mechanism via the <i>β</i> ‐catenin/transcription factor 4/ubiquitin C‐terminal hydrolase L1 axis

BACKGROUND AND PURPOSE: Aminoacylase-1 (ACY1) pathway has emerged as a strategy for reducing myocardial fibrosis in heart failure. We have identified astragaloside II (AS-II) as a potent activator of ACY1 and are investigating its underlying mechanisms in cardiac hypertrophy. EXPERIMENTAL APPROACH: Molecular docking and surface plasmon resonance (SPR) assays were used to screen for ACY1 activators derived from QiShenYiQi (QSYQ) pills. Cardiac hypertrophy was induced by transverse aortic constriction. Echocardiography, histopathology and serum biochemical indicators were detected. Transcriptomics and ACY1 siRNA were performed to explore the downstream mechanisms. Neonatal rat ventricular myocytes were treated with angiotensin II to establish a model of cardiomyocyte hypertrophy. The expression levels of hypertrophic markers and mitochondrial function were assessed. Using cardiac ACY1 overexpression and inhibition was used to investigate the role of angiotensin II in regulating ACY1-mediated pathways. KEY RESULTS: Through virtual screening followed by experimental validation, AS-II was identified as a potent activator of ACY1, demonstrating high binding affinity to human ACY1. In vivo studies showed that AS-II significantly improved cardiac function and attenuated pressure overload-induced cardiac hypertrophy. AS-II enhanced mitochondrial respiration and inhibited hypertrophy in angiotensin II-injured cardiomyocytes. AS-II inhibited β-catenin nuclear translocation and phosphorylation leading to the suppression of transcription factor 4-mediated transcriptional activation of the hypertrophy-associated gene UCHL1. ACY1 inhibition abolished the cardioprotective effects of AS-II, confirming its actions are dependent on ACY1. CONCLUSION AND IMPLICATIONS: AS-II as a novel activator of ACY1 that effectively attenuates cardiac hypertrophy. These findings provide new perspectives for the prevention and treatment of heart failure.