Modulation of glucocorticoid receptor function under iron overload

Area of Science:

• Biochemistry
• Cell Biology
• Toxicology

Background:

• Acute iron overload is a critical condition leading to ferroptosis, inflammation, and multiple organ failure (MOF).
• The glucocorticoid receptor (GR) is a key anti-inflammatory transcription factor, but its role in iron overload toxicity is unclear.

Purpose of the Study:

• To investigate the molecular mechanisms underlying iron overload-induced ferroptosis, focusing on the role of the glucocorticoid receptor (GR).
• To elucidate how iron affects GR function and its implications for ferroptosis and organ damage.

Main Methods:

• Mouse model of acute iron overload (FeSO4 challenge).
• Assessment of HPA axis activation and corticosterone levels.
• Pharmacological inhibition and genetic manipulation of GR.
• RNA sequencing to analyze gene expression changes.
• In vitro assessment of GR-ligand binding in the presence of iron.

Main Results:

• Iron overload activates the HPA axis, increasing corticosterone and upregulating GR-dependent genes in the liver.
• GR appears essential for resisting iron-induced ferroptosis, as GR inhibition or adrenalectomy sensitizes mice to toxicity.
• Dexamethasone (DEX) stimulation of GR fails to protect against iron overload-induced MOF and death.
• RNA sequencing reveals that Fe2+ rapidly and completely inactivates GR biological function by preventing ligand binding.

Conclusions:

• The glucocorticoid receptor (GR) plays a dual role in iron overload: initial protection followed by functional inactivation by iron.
• Iron's direct inactivation of GR, by preventing ligand binding, is a critical mechanism contributing to ferroptosis and organ failure.
• Understanding this GR inactivation is crucial for developing therapeutic strategies against iron overload-induced pathologies.