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Modulation of glucocorticoid receptor function under iron overload.

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|July 3, 2025
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Iron overload triggers ferroptosis and organ failure. While the glucocorticoid receptor (GR) initially protects, iron rapidly inactivates GR, leading to toxicity. This study reveals iron

Keywords:
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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.