Atorvastatin protects cardiomyocytes from doxorubicin toxicity by modulating YAP/TAZ signaling

Doxorubicin (DOX) is a widely used anthracycline chemotherapeutic agent; however, its clinical efficacy is hampered by dose-dependent cardiotoxicity, which can lead to irreversible heart failure. Despite extensive research, effective strategies for preventing or mitigating DOX-induced cardiac injury remain lacking. The Hippo signaling effectors, Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), are known to regulate cardiomyocyte survival, apoptosis, and mitochondrial quality control; however, their role in protecting the heart from DOX toxicity remains unclear. In this study, we investigated whether atorvastatin, a widely prescribed HMG-CoA reductase inhibitor with pleiotropic effects, attenuated DOX-induced cardiomyopathy by modulating the YAP/TAZ signaling axis. In H9c2 cardiomyocytes, DOX suppressed the expression of YAP and TAZ, leading to the downregulation of their downstream targets, Survivin and Park2, and activation of apoptotic cascades. Atorvastatin pretreatment restored YAP/TAZ expression at both mRNA and protein levels and reversed DOX-induced apoptosis. RNA interference-mediated knockdown of YAP or TAZ abolished the protective effects of atorvastatin, confirming the importance of this pathway. In a murine model of DOX cardiotoxicity, atorvastatin preserved left ventricular systolic function, reduced myocardial apoptosis and fibrosis, and restored YAP/TAZ, Survivin, and Park2 expression in the cardiac tissue. These findings suggest that atorvastatin exerts cardioprotective effects by restoring YAP/TAZ-mediated anti-apoptotic and mitochondrial quality control signaling. Our study highlights a novel mechanism via which atorvastatin mitigates DOX-induced cardiotoxicity and supports the therapeutic potential of YAP/TAZ modulation for cardioprotection.