{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T01:44:02Z","timestamp":1783993442162,"version":"3.55.0"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Acute iron overload leads to ferroptosis, in a mouse model of FeSO<jats:sub>4<\/jats:sub> challenge causing lethal shock, associated with inflammation and multiple organ failure (MOF). We investigated molecular aspects causing this phenomenon upon FeSO<jats:sub>4<\/jats:sub> 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 FeSO<jats:sub>4<\/jats:sub>-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<jats:sup>2+<\/jats:sup>, 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.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1605420","type":"journal-article","created":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T04:15:24Z","timestamp":1750220124000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Modulation of glucocorticoid receptor function under iron overload"],"prefix":"10.3389","volume":"16","author":[{"given":"Wanting","family":"Zhu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tineke","family":"Vanderhaeghen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Timmermans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolien","family":"Vandewalle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Eggermont","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolette J. 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