Targeting ferroptosis protects against experimental (multi)organ dysfunction and death
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Abstract
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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- Authors
- Van Coillie, S., Van San, E., Goetschalckx, I., Wiernicki, B., Mukhopadhyay, B., Tonnus, W., Choi, S. M., Roelandt, R., Dumitrascu, C., Lamberts, L., Dams, G., Weyts, W., Huysentruyt, J., Hassannia, B., Ingold, I., Lele, S., Meyer, E., Berg, M., Seurinck, R., Saeys, Y., Vermeulen, A., van Nuijs, A. L. N., Conrad, M., Linkermann, A., Rajapurkar, M., Vandenabeele, P., Hoste, E., Augustyns, K., & Vanden Berghe, T.
- Affiliations
- University of Antwerp (BE)
- Ghent University (BE)
- Muljibhai Patel Urological Hospital (IN)
- University Hospital Carl Gustav Carus (DE)
- VIB-UGent Center for Medical Biotechnology (BE)
- TUM Klinikum (DE)
- Helmholtz Munich (DE)
- Ghent University Hospital (BE)
- ORCID
- Goetschalckx, Ines
- Wiernicki, Bartosz
- Mukhopadhyay, Banibrata
- Tonnus, Wulf
- Roelandt, Ria
- Dumitrascu, Catalina
- Weyts, Wannes
- Huysentruyt, Jelle
- Meyer, Evelyne
- Berg, Maya
- Seurinck, Ruth
- Saeys, Yvan
- Vermeulen, An
- Conrad, Marcus
- Linkermann, Andreas
- Rajapurkar, Mohan
- Vandenabeele, Peter
- Hoste, Eric
- Augustyns, Koen
- Vanden Berghe, Tom
- Venue
- Nature Communications
- Published
- 2022-02-24
- Volume
- 13
- Issue
- 1
- Pages
- 1046-1046
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8873468
- OpenAlex
- W4213442676
- Cited by
- 186
- References
- 11
- Citations by year
- 2026: 33 · 2025: 42 · 2024: 48 · 2023: 41 · 2022: 15 · 2017: 1 · 2016: 3 · 2015: 1 · 2014: 1
- FWCI
- 23.72
- Type
- journal article
- Language
- en
- Update notices
- correction (2025-09-18)
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
- Site cant be reached (submittedVersion, cc-by)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
- Funders
- European Commission (HORIZON2020)
- Deutsche Forschungsgemeinschaft (SFB-TRR 205, CO 291/7–1, BOF16/MET_V/007, TRR127, SFB TRR127, IRTG2251, 324141047)
- Bundesministerium für Bildung und Forschung (/2018, 03VP04260)
- Fonds Wetenschappelijk Onderzoek (1181917N, G0B9620N, G0C0119N, F/2020/1505, F/2016/865, S001522N, G0C7618N, G0B7118N, BOF09/01M00709, 30837538, BOF16/MET_V/007, CU2018TEA457A103, G049720N, G0E0416N, FWO Grant 30826052, BOF14/GOA/019, G0A9322N, 30826052)
- Universitair Ziekenhuis Gent
- Universiteit Gent (BOF09/01M00709, FAF-F/2016/865, F2012/IOF, BOF16/MET_V/007, 01M00709, F2012/IOF-Advanced/001)
- Vlaamse Interuniversitaire Raad (30826052, G.0C76.18N, G.0B71.18N, F/2016/865, G.0B96.20N, BOF16/MET_V/007, CU2018TEA457A103, F/2020/1505)
- Fondation Charcot (FAF-C/2018/1250)
- Universiteit Antwerpen (32254, G0C0119N)
- Kom op tegen Kanker (30837538)
- Vlaamse regering (BOF09/01M00709, BOF16/MET_V/007, 30837538)
- Ministry of Science and Higher Education of the Russian Federation (075-15-2019-1933, 075-15-)
- Fondation contre le Cancer (G.0C76.18N, G.0B71.18N, CU2018TEA457A103, 30826052, G.0B96.20N, BOF16/MET_V/007, FAF-C/2018/1250, F/2016/865, F/2020/1505, FAF-F/2016/865)
- VLIRUOS (30837538, TEAM2018‐01‐137)
- Bijzonder Onderzoeksfonds UGent (iBOF20/IBF/039 ATLANTIS, BOF16/MET_V/007, Methusalem BOF16/MET_V/007)
- H2020 European Research Council (884754)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Keywords
- ferroptosis, multiple organ failure, catalytic iron, lipid peroxidation, sepsis, ICU mortality, free radical toxicity, cell death, organ damage
- MeSH terms
- Ferroptosis, Animals, Humans, Iron, Multiple Organ Failure, Lipid Peroxidation, Cell Death, Mice
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