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Hypothesising that decreased macrophage viability in an oxidative environment could be a contributing factor to the pathophysiology of CD, we found that monocyte-derived macrophages from individuals with active CD (but not those in clinical disease remission) have increased sensitivity to cell death induced by H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    . Molecular biology and pharmacological studies ruled out apoptosis and necroptosis, while increased lipid peroxidation and surface expression of the transferrin receptor implicated ferroptosis as the mechanism of the H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    -induced cell death: this was supported by suppression of H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    -cytotoxicity by liproxstatin-1, a pharmacological inhibitor of ferroptosis. Selenoproteins are important antioxidants, and selenium deficiency can be a feature of CD. Despite normal dietary intake of selenium, monocyte-derived macrophages and intestinal macrophages in individuals with CD had decreased protein and\/or mRNA expression of the selenoprotein, glutathione peroxidase (GPx)-1. Knockdown of GPx1 in macrophages from healthy volunteers resulted in increased H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    -induced cell death reminiscent of that observed with macrophages from CD. In summary, monocyte-derived macrophages from individuals with CD have increased susceptibility to H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    -induced ferroptosis cell death, that may be facilitated, at least in part, by reduced expression of the antioxidant GPx1. We suggest that reduced GPx1 in monocytes recruited to the gut and intestinal macrophages renders these cells vulnerable to reactive oxygen species-evoked ferroptosis cell death and that unraveling the participation of this pathway in Crohn\u2019s disease may reveal novel therapeutic approaches to this chronic condition.\n                  <\/jats:p>","DOI":"10.1038\/s41419-024-07289-y","type":"journal-article","created":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T12:43:35Z","timestamp":1734525815000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["GPx1 deficiency confers increased susceptibility to ferroptosis in macrophages from individuals with active Crohn\u2019s disease"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8389-0273","authenticated-orcid":false,"given":"James A.","family":"Sousa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca E.","family":"Callejas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eve","family":"Higgins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aydin","family":"Herik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Andonian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Munazza","family":"Yousuf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pina","family":"Colarusso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maitreyi","family":"Raman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0557-8210","authenticated-orcid":false,"given":"Derek M.","family":"McKay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,18]]},"reference":[{"key":"7289_CR1","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1007\/s00011-020-01398-y","volume":"69","author":"TC Moreira Lopes","year":"2020","unstructured":"Moreira Lopes TC, Mosser DM, Goncalves R. 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