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Paradoxically, the daily iron required to fuel the production red blood cell (RBC) and prevent anemia is provided through its recycling from senescent RBC. This is achieved by splenic red pulp macrophages (RPM) that extract iron from the heme groups of hemoglobin (Hb). How these professional erythrophagocytic macrophages prevent intracellular iron flux from inducing cell death via ferroptosis is unknown. Here we show that SPI-C, the master transcriptional regulator of the erythrophagocytic lineage, orchestrates two redundant anti-ferroptosis pathways. One supports glutathione synthesis, via NF-E2-related factor 2 (NRF2), and the other relies on bilirubin production by biliverdin reductase A (BVRA). Genetic ablation of both pathways, but not either alone, sensitizes erythrophagocytic macrophages to ferroptosis, depletes RPM and increases the severity of iron deficiency anemia in mice. These findings reveal a central physiologic role of ferroptosis in the control of macrophage function, iron homeostasis and iron-deficiency anemia.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"order\">\n                    <jats:list-item>\n                      <jats:p>SPI-C enforces the antioxidant metabolic program of RPM.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>SPI-C controls bilirubin production by biliverdin reductase A.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Bilirubin protects erythrophagocytic macrophages from ferroptosis.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Ferroptosis protection supports iron-recycling macrophages and limit iron deficiency anemia.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.22.732688","type":"posted-content","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T17:25:24Z","timestamp":1782494724000},"source":"Crossref","is-referenced-by-count":0,"title":["Ferroptosis is a Physiologic Vulnerability of Iron-Recycling Macrophages"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5927-790X","authenticated-orcid":false,"given":"Miguel","family":"Mesquita","sequence":"first","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine (GIMM), Avenida Professor Egas Moniz \u2013 1649-035 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Pires","sequence":"additional","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine (GIMM), Avenida Professor Egas Moniz \u2013 1649-035 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2124-5712","authenticated-orcid":false,"given":"Sara","family":"Violante","sequence":"additional","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine (GIMM), Avenida Professor Egas Moniz \u2013 1649-035 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0973-5460","authenticated-orcid":false,"given":"Jamil Zola","family":"Kitoko","sequence":"additional","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine (GIMM), Avenida Professor Egas Moniz \u2013 1649-035 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martim","family":"Costa","sequence":"additional","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine (GIMM), Avenida Professor Egas Moniz \u2013 1649-035 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2333-7170","authenticated-orcid":false,"given":"Sonia Trikha","family":"Rastogi","sequence":"additional","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine (GIMM), Avenida Professor Egas Moniz \u2013 1649-035 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8106-6324","authenticated-orcid":false,"given":"Rui","family":"Martins","sequence":"additional","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine (GIMM), Avenida Professor Egas Moniz \u2013 1649-035 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4639-698X","authenticated-orcid":false,"given":"Silvia","family":"Cardoso","sequence":"additional","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine (GIMM), Avenida Professor Egas Moniz \u2013 1649-035 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Tanqueiro","sequence":"additional","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine (GIMM), Avenida Professor Egas Moniz \u2013 1649-035 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9075-2238","authenticated-orcid":false,"given":"Ana","family":"Figueiredo","sequence":"additional","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine (GIMM), Avenida Professor Egas Moniz \u2013 1649-035 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2258-736X","authenticated-orcid":false,"given":"Nelli","family":"Blank-Stein","sequence":"additional","affiliation":[{"name":"Developmental Biology of the Immune System, Life & Medical Sciences (LIMES) Institute, University of Bonn; 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