ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1605420
Modulation of Glucocorticoid Receptor Function under Iron Overload
Provisionally accepted
Wanting Zhu1,2
Tineke Vanderhaeghen1,2
Steven Timmermans1,2
Jolien Vandewalle1,2
Melanie Eggermont1,2
Nicolette Jeanette Dorothy Verhoog3
Claude Libert1,2*- 1Flemish Institute for Biotechnology, Ghent, Belgium
- 2Ghent University, Ghent, East Flanders, Belgium
- 3Stellenbosch University, Stellenbosch, Western Cape, South Africa
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Acute iron overload leads to ferroptosis, in a mouse model of FeSO4 challenge causing lethal shock, associated with inflammation and multiple organ failure (MOF). We investigated molecular aspects causing this phenomenon upon FeSO4 overload, with a focus on the glucocorticoid receptor (GR), an important anti-inflammatory transcription factor. We report that Fe overload activates the HPA axis, leading to corticosterone increases in the blood, acutely causing upregulation of GR-dependent genes in liver. Using a GR blocker, mice with a reduced GR dimerization potential and removal of adrenal glands sensitizes mice for Fe-induced toxicity, GR appears essential to resist ferroptosis. However, stimulating GR with DEX is unable to protect mice against FeSO4-induced MOF and death. This dilemma is shown, by RNA sequencing, to be the result of a quick and complete inactivation of GR biological function by Fe 2+ , shortly after the initial activation. This inactivity of GR seems to be the result of a complete lack of GR to bind its ligand. We discuss the possible mechanism and complications for ferroptosis progression during diseases.
Keywords: Iron, Glucocorticoids, ferroptosis, function, Critical illnesses
Received: 03 Apr 2025; Accepted: 29 May 2025.
Copyright: © 2025 Zhu, Vanderhaeghen, Timmermans, Vandewalle, Eggermont, Verhoog and Libert. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Claude Libert, Ghent University, Ghent, 9000, East Flanders, Belgium
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