Iron (Fe) is a vital element for almost all organisms due to its ability to donate and accept electrons with relative ease. It serves as a cofactor for many proteins and enzymes necessary for the proper use of oxygen and energy generation, as well as its deregulation is related to the processes of oxidative stress and iron-mediated cell death called FERROPTOSIS. It is a new type of cell death that was discovered in recent years and is usually accompanied by a large amount of iron accumulation and lipid peroxidation during the cell death process. Refractory Epilepsy (RE) occurs in approximately 30-40% of patients with epilepsy and has a higher risk of sudden unexpected death in epilepsy (SUDEP). Since seizures are considered hypoxic-ischemic episodes that trigger intracellular oxidative stress, recent studies showed that repetitive spontaneous seizures can be related to an increase in oxidative stress and reactive oxygen derivatives (ROS) production in a hypoxia inducible factor 1 alpha (HIF-1)-dependent manner. This process causes lipid peroxidation, protein oxidation, and destruction of nuclear genetic material, enzyme inhibition, and cell death with an increase of intracellular free iron (Fe2+) concentration. Repetitive tonic-clonic seizures (GTCS) are the main risk factor of SUDEP. The hypoxic stress induced by seizure results in neurodegeneration with iron accumulation as well as cardiogenic dysfunctions related to Iron Overload and Cardiomyopathy (IOC). ROS production, severe lipid peroxidation can be an effective inducer of the named “epileptic heart” (EH), which is characterized by altered autonomic function and a high risk of malignant or fatal bradycardia. Our studies demonstrated that recurrent experimental seizures induce in cardiomyocytes: HIF-1 activation, P-glycoprotein overexpression, low expression of Inwardly Rectifying Potassium (Kir) Channels (Kir), hemosiderin precipitation, and functionally the developing of long Q-T interval, severe bradycardia associated with high spontaneous death ratio. It is postulated that severe seizures induce systemic hypoxia and heart FERROPTOSIS associated with SUDEP. It is proposed that inhibition of FERROPTOSIS with ROS scavenger’s, iron chelators, antioxidants, could provide reduce epileptic dependent neurodegeneration as well as Iron Overload and Cardiomyopathy (IOC ) associated with SUDEP risk, by heart Ferroptosis protection.