Tectorigenin attenuates cardiac hypertrophy via USP9X/MCL1-mediated mitochondrial stabilization

Area of Science:

• Cardiovascular Biology
• Mitochondrial Medicine
• Pharmacology

Background:

• Pathological cardiac hypertrophy is a major therapeutic challenge, often driven by mitochondrial dysfunction and maladaptive remodeling.
• Current treatments for cardiac hypertrophy have limitations in addressing underlying mitochondrial issues.

Purpose of the Study:

• To investigate the cardioprotective effects of tectorigenin (Tec) in transverse aortic constriction (TAC)-induced cardiac hypertrophy.
• To elucidate the underlying molecular mechanisms, particularly focusing on mitochondrial homeostasis and the USP9X-MCL1 axis.

Main Methods:

• In vivo studies using a mouse model of TAC-induced cardiac hypertrophy.
• In vitro experiments using phenylephrine-stimulated cardiomyocytes.
• Analysis of mitochondrial function, cell size, fibrosis, and protein expression (MCL1, USP9X).
• Gene silencing techniques to assess the roles of MCL1 and USP9X.

Main Results:

• Tec administration improved survival, reduced cardiac dysfunction, hypertrophy, and fibrosis in TAC mice.
• Tec inhibited cardiomyocyte enlargement and mitochondrial impairment in vitro.
• Tec stabilized mitochondrial protein MCL1 via USP9X-mediated deubiquitination, independent of PI3K-AKT signaling.
• Silencing MCL1 or USP9X abolished Tec's protective effects.

Conclusions:

• Tectorigenin exhibits significant cardioprotective effects against pathological hypertrophy.
• Tec acts through a novel USP9X-MCL1-mitochondria axis to maintain mitochondrial integrity.
• Tec represents a promising mitochondria-targeted therapeutic strategy for heart failure, distinct from traditional survival pathways.