Nicotinamide riboside promoted cardiac energetics and alleviated doxorubicin-induced cardiotoxicity via SIRT1/ERRα signal in human pluripotent stem cells-derived cardiomyocytes

Doxorubicin is an antineoplastic chemotherapeutic drug that causes cardiotoxicity with energetics impairment and oxidative stress. Nicotinamide ribose (NR) is the precursor of NAD+ and has demonstrated beneficial effects in several animal models of cardiovascular disease. This study aimed to test the role and mechanism of nicotinamide ribose on human induced pluripotent stem cell-differentiated cardiomyocytes (HiPSCs-CMs) under normal and doxorubicin-treated states. We found that NR increased mitochondrial fusion and integrity in HiPSCs-CMs, promoted mitochondrial oxidative phosphorylation levels and ATP output, and increased ERRα expression. Inhibition of SIRT1 reversed the beneficial effects of NR. Protein-protein docking and immunoprecipitation showed that SIRT1 may bind directly to ERRα and regulates ERRα expression. Agonism of SIRT1 shows a facilitating effect on mitochondrial energetics, an effect that is counteracted by inhibitors of ERRα. Furthermore, NR promotes mitochondrial energetics via SIRT1/ERRα in doxorubicin-induced cardiac cytotoxicity, reduces cardiomyocyte oxidative stress injury, and attenuates apoptosis. Our findings reveal beneficial effects of nicotinamide ribose on HiPSCs-CMs under normal or disease conditions. In conclusion, our study provides the basis for advancing the clinical translation of nicotinamide ribose into the clinic.