Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-28718-6
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Funding
- Strategic Basic Research Foundation Flanders, IRONIX [S001522N]
- Research Foundation Flanders [1181917N, 1181919N, G0B7118N, G0C0119N, G049720N, G0C7618N, G0B718N, G.0B9620N, G0A9322N]
- Excellence of Science MODEL-IDI
- EOS INFLADIS
- Consortium of excellence at University of Antwerp INFLA-MED
- Industrial research Fund from University of Antwerp
- Industrial Research Fund from Ghent University [F2012/IOF-Advanced/001]
- UGent Special research fund [BOF14/GOA/019]
- Foundation against cancer [FAF-F/2016/865, FAF-C/2018/1250, F/2020/1505]
- Charcot Foundation
- VLIRUOS [TEAM2018-01-137]
- iBOF20/IBF/039 ATLANTIS
- FWO-SBO [S001522N]
- Flemish Institute of Biotechnology VIB
- Methusalem [BOF16/MET_V/007]
- German Research Foundation [324141047, SFB-TRR 127, SFB-TRR 205, IRTG 2251]
- Deutsche Forschungsgemeinschaft [CO 291/7-1]
- German Federal Ministry of Education and Research VIP+program [NEUROPROTEKT 03VP04260]
- Ministry of Science and Higher Education of the Russian Federation [075-15-2019-1933]
- European Research Council under the European Union [GA 884754]
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The development of multiorgan dysfunction syndrome (MODS) is the most common cause of death in the intensive care unit (ICU). Catalytic iron is associated with ICU mortality and may induce excessive lipid peroxidation, leading to cellular toxicity and multiorgan dysfunction. Blocking lipid peroxidation with a ferrostatin-analogue can protect mice from injury and death in experimental non-septic MODS.
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.
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