AUTHOR=Zhu Wanting , Vanderhaeghen Tineke , Timmermans Steven , Vandewalle Jolien , Eggermont Melanie , Verhoog Nicolette J. D. , Libert Claude 

TITLE=Modulation of glucocorticoid receptor function under iron overload

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1605420

DOI=10.3389/fimmu.2025.1605420

ISSN=1664-3224

ABSTRACT=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 Fe2+, 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.