Modulation of Glucocorticoid Receptor Function under Iron Overload

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. Since a GR blocker, mutant GR mice and removal of adrenals sensitize mice for Fe-induced toxicity, GR appears essential to resist ferroptosis, and stimulation appears an interesting option to deal with ferroptosis. However, DEX treatment is unable to protect mice against FeSO4- induced death and MOF. This dilemma is shown, by RNA-seq, 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 ligand. We discuss the possible mechanism and complications for ferroptosis progression during diseases Overall design: RNA-seq profiling of mouse livers after a total of 8 hours: 6 hours iron treatment (FeSO4) + 2 hours of DEX and respective controls, for a total of 4 groups with 3 biological replicates per group