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Cyntia Gracesella Patintingan,1 Melva Louisa,2 Vetnizah Juniantito,3 Wawaimuli Arozal,2 Silmi Hanifah,1 Septelia Inawati Wanandi,4 Rajarajan Thandavarayan5 1Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; 2Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; 3Department of Veterinary Clinic Reproduction and Pathology, Faculty of Veterinary Medicine, Agriculture Institute of Bogor, Bogor, Indonesia; 4Department of Biochemistry and Molecular Biology, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia; 5Department of Cardiovascular Sciences Houston Methodist Research Institute, Houston, TX, USACorrespondence: Melva Louisa, Department of Pharmacology and Therapeutics Faculty of Medicine, Universitas Indonesia, Jakarta, 10430, Indonesia, Tel +62-21-31930481, Email melva.louisa@gmail.comBackground: Doxorubicin, an anthracycline class of anticancer, is an effective chemotherapeutic agent with serious adverse effects, mainly cardiotoxicity. Several possible causes of doxorubicin cardiotoxicity are increased oxidative stress, nucleic acid and protein synthesis inhibition, cardiomyocyte apoptosis, and mitochondrial biogenesis disruptions. Moringa oleifera (MO), a naturally derived medicine, is known for its antioxidative properties and activity in alleviating mitochondrial dysfunction. To determine the potency and possible cardioprotective mechanism of MO leaves aqueous extract via the mitochondrial biogenesis pathway in doxorubicin-induced rats.Methods: Twenty-four Sprague-Dawley rats were divided into four groups of six. The first group was normal rats; the second group was treated with doxorubicin 4 mg/kg BW intraperitoneally once weekly for four weeks; the third and fourth groups were treated with doxorubicin 4 mg/kg BW intraperitoneally once weekly, and MO leaves extract at 200 mg/kg BW or 400 mg/kg BW orally daily, for four weeks. At the end of the fourth week, blood and cardiac tissues were obtained and analyzed for cardiac biomarkers, mitochondrial DNA copy number, mRNA expressions of peroxisome-activated receptor-gamma coactivator-1 alpha (PGC-1α), the nuclear factor erythroid 2-related factor 2 (Nrf2), superoxide dismutase 2 (SOD2), caspase 3, the activity of glutathione peroxidase (GPx), levels of 8-hydroxy-2-deoxyguanosine (8-OH-dG), and malondialdehyde.Results: MO leaves extract was shown to decrease biomarkers of cardiac damage (LDH and CK-MB), malondialdehyde levels, and GPx activity. These changes align with the reduction of mRNA expressions of caspase-3, the increase of mRNA expressions of PGC-1α and Nrf2, and the elevation of mitochondrial DNA copy number. MO leaves extracts did not influence the mRNA expressions of superoxide dismutase 2 (SOD2) or the levels of 8-OH-dG.Conclusion: Moringa oleifera leaves extract ameliorates doxorubicin-induced cardiotoxicity by reducing apoptosis and restoring gene expression of PGC-1α and Nrf2, a key regulator in mitochondrial biogenesis.Keywords: anthracycline, DNA damage, mitochondrial DNA, Moringa oleifera Lam, oxidative stress