Study of the contribution of different modes of regulated necrosis in acute liver injury and lethal shock 

Cell death research was revitalized by the understanding that necrosis can occur in a highly regulated and genetically controlled manner. Necrotic cell death is a kind of cell death in which cells release their cellular content in the surrounding tissue resulting in inflammation and tissue degradation, in contrast to apoptotic cell death. We now realize that multiple forms of regulated necrosis exist. A new type of regulated necrosis that is catalyzed by iron was recently unraveled and is now referred to as ferroptosis. A number of hereditary conditions have been found that perturb body iron homeostasis and promote pathological deposition of the metal resulting in organ damage in liver, heart, pancreas, thyroid and the central nervous system. For this reason, iron chelators have been implemented or proposed as treatments for these diseases. Because iron is an essential metal for the overall functioning of organisms, whole body scavenging of iron is not preferable due to its expected detrimental side effects. In view of the recent experimental findings that inhibitors of ferroptosis (called ferrostatins) can protect against an experimental model of renal and liver failure, this project will focus on the mechanistic study of ferroptosis, the development of iron-catalyzed acute liver models and the validation of our second generation of ferrostatin analogues in these acute liver failure models.