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bioRxiv · 10.1101/2025.11.06.683842

CARP Protects Against Doxorubicin-induced Cardiotoxicity through NRF1-driven Mitochondrial Homeostasis

Zhong, D.·Xu, X.·Feng, T.·Zhang, W.·Luo, F.·Guo, J.·Luo, Z.·Chen, R.·Wang, Y.·Ma, G.
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Abstract

AimsDoxorubicin (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 resultsCardiac-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 (mtDNA 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 CARPs role 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. ConclusionCARP safeguards against DIC by maintaining mitochondrial homeostasis via NRF1 signaling, positioning it as a promising therapeutic target for DOX-induced cardiomyopathy.

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Zhong, D., Xu, X., Feng, T., Zhang, W., Luo, F., Guo, J., Luo, Z., Chen, R., Wang, Y., Ma, G.. 2025-11-06. CARP Protects Against Doxorubicin-induced Cardiotoxicity through NRF1-driven Mitochondrial Homeostasis. https://doi.org/10.1101/2025.11.06.683842

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