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

Pathological cardiac hypertrophy, driven by mitochondrial dysfunction and maladaptive remodeling, remains a therapeutic challenge. This study explores the cardioprotective properties of tectorigenin (Tec) in the context of transverse aortic constriction (TAC)-induced hypertrophy, focusing on mitochondrial homeostasis. In animal models, administration of Tec improved survival rates, reduced cardiac dysfunction, and decreased hypertrophy and fibrosis in TAC mice, while preserving mitochondrial function. In in vitro experiments, Tec was found to inhibit the enlargement of cardiomyocytes and mitochondrial impairment induced by phenylephrine. The underlying mechanism revealed that Tec stabilizes MCL1, a key regulator of mitochondrial integrity, by promoting its deubiquitination through USP9X, thus preventing its degradation without relying on the PI3K-AKT signaling pathway. Notably, silencing either MCL1 or USP9X negated the anti-hypertrophic and antioxidant effects of Tec, underscoring their critical roles in this process. These findings position Tec as a novel modulator of the USP9X-MCL1-mitochondria axis, suggesting a new therapeutic approach to separate pathological remodeling from mitochondrial dysfunction in cardiac hypertrophy. By circumventing traditional survival pathways, Tec represents a mitochondria-focused strategy to slow the progression of heart failure, linking the pharmacology of natural compounds with the resilience of targeted organelles.