Objective To observe the effect of iron overload on the cardiac function of mice and cardiac myocytes ferroptosis of rats, and explore the mechanism of action of iron transporter receptor (TFRC) in cardiac myocytes ferroptosis of rats. Methods Fourteen C57BL/6J mice were randomly divided into normal-iron diet (NID) group and high-iron diet (HID)group (7 each), fed with normal diet or high-iron diet for 8 weeks, respectively. The mice cardiac function was then detected by echocardiography; The content of malondialdehyde (MDA) in the heart was detected with ELISA; Masson staining was performed to detect the cardiac fibrosis; Propidium iodide (PI) staining and lipophilic fluorescent dye (C11) were used to detect the cell mortality and the content of lipid peroxide. The effect was observed of ferric ammonium citrate (AIC) and ferroptosis inhibitor ferrostatin-1 (Fer-1) on the cardiac myocytes of H9C2 rat. H9C2 cells were treated with AIC and ferroptosis inducer Erastin,Western blotting was performed to detect the expression level of TFRC and glutathione peroxidase 4 (GPX4) protein, qRT-PCR was used to detect the mRNA level; at the same condition, small interfering RNA was applied to knock-down the expression of TFRC,detect the mortality of H9C2 cells and the content of lipid peroxide. Results Compared with mice in NID group, the mice in HID group showed obviously increased interventricular septal thickness (IVSd), left ventricular posterior wall thickness (LVPWd), MDA relative content and area of collagen deposition (0.96±0.12 vs. 0.73±0.09, 1.18±0.28 vs. 0.84±0.07, 2.08±0.8 vs. 1.00±0.50,4.04±0.60 vs. 1.00±0.21, P<0.05); But no significant difference between the two groups on left ventricular ejection fraction and shortening fraction. Treated with 500 μmol/L AIC, the death rate and lipid peroxide content of H9C2 increased obviously(33.73%±1.20% vs. 2.30%±1.73%, 5.36±0.06 vs. 1.00±0.19, P<0.05), while after treatment with Fer-1, the death rate and lipid peroxide content of H9C2 decreased markedly (19.63%±0.81% vs. 33.73%±1.20%, 2.03±0.12 vs. 5.36±0.06, P<0.05). Treated with 500 μmol/L AIC, the expression level increased obviously of TFRC in H9C2 cell (P<0.05), while knocked-down of TFRC, the cell death rate and the content of lipid peroxide induced by high-iron decreased markedly (P<0.05). Under inducement of Erastin,the expression levels of TFRC and GPX4 protein in H9C2 cells obviously up- and down-regulated, respectively; and after knocked-down of TFRC, the cell death rate induced by Erastin decreased markedly (P<0.05). Conclusions HID may induce the damage of myocardial ferroptosis, and TFRC participated in the pathologic process induced by iron overload, which may be as a new target point for the treatment of heart diseases.