Targeting ferroptosis protects against multiorgan dysfunction and death.

Abstract Approximately half of all critically ill patients in the intensive care unit (ICU) develop multiorgan dysfunction1, which is responsible for 30% of deaths worldwide2,3. Besides life-supporting treatments, no cure exists for multiorgan dysfunction and its mechanisms are still poorly understood4. Catalytic iron is a detrimental factor associated with ICU mortality5,6 and is known to cause free radical-mediated cellular toxicity7. As such, catalytic iron is thought to induce excessive lipid peroxidation7, the main characteristic of an iron-dependent type of cell death conceptualized as ferroptosis8,9. Here we show that pharmacological targeting of ferroptosis with our most potent ferrostatin-analogue10 rescues from death in acute single and multiorgan dysfunction in mice, but not sepsis. Daily monitoring of critically ill ICU patients revealed that the peak level of malondialdehyde, reflecting excessive lipid peroxidation, correlates with multiorgan dysfunction and death. Our results demonstrate that ferroptosis targeting is life-saving in experimental models of critical illness and that monitoring of malondialdehyde can allow patient stratification. Therefore, controlling the extent of ferroptosis in non-septic patients with multiorgan dysfunction could become a novel treatment for one of the major causes of global deaths.