CARP Protects Against Doxorubicin-induced Cardiotoxicity through NRF1-driven Mitochondrial Homeostasis
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Aims
Doxorubicin (DOX), a highly effective anthracycline chemotherapeutic agent, is limited by its dose-dependent cardiotoxicity. This study investigates the cardioprotective mechanisms of cardiac adriamycin responsive protein (CARP) and its underlying mechanisms in DOX-induced cardiotoxicity (DIC).
Methods and results
Cardiac-specific CARP transgenic and wild-type mice were subjected to a DIC model. Cardiac function was assessed via echocardiography, histopathology, and transmission electron microscopy (TEM). In vitro , DOX-treated cardiomyocytes overexpressing CARP were analyzed for oxidative stress (ROS levels), mitochondrial function (mt DNA copy number etc.), and mitochondrial-related proteins (Western blot). CARP-NRF1 interaction was validated by co-immunoprecipitation (Co-IP), and NRF1 siRNA knockdown was performed to assess the role of CARP in mitochondrial homeostasis. CARP overexpression markedly alleviated DOX-induced cardiac dysfunction and mitochondrial damage, restoring mitochondrial dynamics and mitophagy. Mechanistically, CARP directly interacted with NRF1, and NRF1 knockdown ameliorated CARP-mediated cardioprotection in DIC.
Conclusion
CARP safeguards against DIC by maintaining mitochondrial homeostasis via NRF1 signaling, positioning it as a promising therapeutic target for DOX-induced cardiomyopathy.
