The most common cause of death in the intensive care unit (ICU) is the development of multiorgan dysfunction syndrome (MODS). Besides life-supporting treatments, no cure exists, and its mechanisms are still poorly understood. Catalytic iron is associated with ICU mortality and is known to cause free radical-mediated cellular toxicity. It is thought to induce excessive lipid peroxidation, the main characteristic of an iron-dependent type of cell death conceptualized as ferroptosis. Here we show that the severity of multiorgan dysfunction and the probability of death are indeed associated with plasma catalytic iron and lipid peroxidation. Transgenic approaches underscore the role of ferroptosis in iron-induced multiorgan dysfunction. Blocking lipid peroxidation with our highly soluble ferrostatin-analogue protects mice from injury and death in experimental non-septic multiorgan dysfunction, but not in sepsis-induced multiorgan dysfunction. The limitations of the experimental mice models to mimic the complexity of clinical MODS warrant further preclinical testing. In conclusion, our data suggest ferroptosis targeting as possible treatment option for a stratifiable subset of MODS patients.
GrantsGerman Research Foundation (DFG) German Federal Ministry of Education and Research VIP+program Ministry of Science and Higher Education of The Russian Federation European Research Council (ERC) FWO Strategic Basic Research Foundation Flanders, IRONIX Methusalem Flemish Institute of Biotechnology VIB FWO-SBO iBOF20/IBF/039 ATLANTIS VLIRUOS Charcot Foundation Foundation against cancer UGent Special research fund Industrial Research Fund from Ghent University Industrial research Fund from University of Antwerp Consortium of excellence at University of Antwerp INFLA-MED EOS INFLADIS Excellence of Science MODEL-IDI