Trilobatin Ameliorates Myocardial Hypertrophy by Enhancing Mitophagy Through Activation of the Sentrin-Specific Protease 1/Sirtuin 3 Axis in Spontaneously Hypertensive Rats.

Myocardial hypertrophy represents a maladaptive response in numerous cardiovascular disorders, and potentiating mitophagy has emerged as a potential therapy. Trilobatin (TLB) possesses multiple pharmacological properties, including the alleviation of cardiotoxicity. However, it remains uncertain whether TLB exerts anti-hypertrophic effects or, if so, by what mechanisms. This study was designed to determine whether TLB can attenuate hypertrophy and to elucidate the underlying pathways, focusing on mitophagy. We employed in vivo spontaneously hypertensive rats (SHR) and in vitro angiotensin II-stimulated cardiomyocytes to evaluate anti-hypertrophic effects. A comprehensive approach was employed, incorporating echocardiography, histological staining, transmission electron microscopy observations, and immunofluorescence to assess phenotypic changes. RNA sequencing, western blotting, immunofluorescence, and ELISA were utilized to elucidate the underlying mechanisms. Additionally, molecular docking, molecular dynamics simulations, and siRNA transfection techniques were applied to identify the target of TLB. The results showed that TLB markedly alleviated hypertrophy in SHR and inhibited angiotensin II-induced cardiomyocyte hypertrophy. Mechanistically, TLB enhanced mitophagy and reduced oxidative stress via activation of the sentrin-specific protease 1/sirtuin 3 (SENP1/SIRT3) axis, with direct binding to SENP1. Crucially, SENP1 knockdown abolished TLB's cardioprotective effects, confirming SENP1 as a pivotal mediator. Our findings indicate that TLB exerts anti-hypertrophic effects by promoting mitophagy and suppressing oxidative injury through the SENP1/SIRT3 axis, highlighting SENP1 as a promising therapeutic target for myocardial hypertrophy.