Arterial media calcification (AMC) is the deposition of calcium-phosphate crystals in the medial layer of the arterial wall and is an independent risk factor for cardiovascular morbidity/mortality. Efficient treatment for this lethal, highly prevalent pathology is lacking. Vascular smooth muscle cells, the key cell type in AMC, under oxidative stress transdifferentiate into cells with bone-forming capacity or die. It is not clear, however, which cell death type is most important. Ferroptosis, a recently discovered regulated type of cell death, is the result of iron-catalyzed, oxidative stress-induced membranous lipid peroxidation. Several arguments from literature and preliminary results from our lab put forward a role for iron accumulation, lipid peroxidation/ferroptosis in the process of AMC. This project aims to further substantiate this role by (i) exploring the AMC-aggravating effect of iron and (ii) the genetic induction of vascular smooth muscle cell-lipid peroxidation, in order to put forward lipid peroxidation as a novel target to treat AMC. Lipid peroxidation can be prevented by membranous radical trapping. Since potent membranous radical traps were developed in-house, we will have the unique opportunity to test these patented molecules for their ability to halt AMC. AMC-therapy development often stumbled over osseous side-effects (crystal deposition was inhibited in bone next to vessels). Membranous radical trapping therapy should overcome this problem.