<p>Previous studies suggest that ferroptosis is involved in cardiovascular diseases. The aim of the present study is to investigate the causal relationship between angiotensin II type 1 and type 2 receptors (AT_1/2R) activities and mitochondrial dysfunction in induction of cardiomyocyte ferroptosis. Human AC16 cardiomyocytes were first pre-treated with an AT_1/2R blockers, before stimulated with angiotensin II (Ang II) for 24 h. The redox status of the cardiomyocytes were assessed by measuring the cellular malondialdehyde (MDA), superoxide dismutase (SOD), and Nicotinamide-adenine dinucleotide phosphate, (NADPH) levels using biochemical methods. Mitochondrial reactive oxygen specifics (mitROS), mitochondrial memebrane potential, and Fe²⁺ levels were determined using flow cytometry. The signaling pathways, including the glutathione peroxidase 4 (GPX4), heme oxygenase-1 (HO-1), sirtuin1, and ferroptosis suppressor protein 1 (FSP1)-coenzyme Q10 (CoQ10) pathways, were evaluated using western blotting. Our results demonstrated that Ang II significantly elevated the levels of MDA, Fe²⁺, mitoROS, and FtMt and markedly reduced SOD, NADPH, mitochondrial membrane potential, GPX4, HO-1, Sirt1, SFXN1, Nrf2, and FSP1 levels in cardiomyocyte, which were reversed by blockade of AT_1/2R. Our results suggest that AT_1/2R signaling can induce myocardial ferroptosis by impairing mitochondrial function via multiple signaling pathways, including the cyst (e)ine /GSH/GPX4 axis and FSP1/coenzyme Q10 (CoQ10) axis.</p>