{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T03:43:53Z","timestamp":1775965433834,"version":"3.50.1"},"posted":{"date-parts":[[2025,3,15]]},"group-title":"Immunology","reference-count":56,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,15]],"date-time":"2025-03-15T00:00:00Z","timestamp":1741996800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Immune suppression heightens the risk for fungal infections, but the mechanisms that result in clinical disease are poorly understood. Here we demonstrate that macrophage ferroptosis, an iron-dependent form of regulated cell death, inhibits\n                  <jats:italic>Aspergillus fumigatus<\/jats:italic>\n                  (\n                  <jats:italic>Af<\/jats:italic>\n                  ) killing. In a mouse tracheal transplant model of\n                  <jats:italic>Af<\/jats:italic>\n                  infection, we observed an increase in macrophage lipid peroxidation, a decreased expression of negative ferroptosis regulators\n                  <jats:italic>Gpx4<\/jats:italic>\n                  and\n                  <jats:italic>Slc7a11<\/jats:italic>\n                  , and an increase in positive regulators\n                  <jats:italic>Ptgs2<\/jats:italic>\n                  and\n                  <jats:italic>Nox2<\/jats:italic>\n                  , relative to syntransplants. Depletion of macrophages in transplant recipients decreased\n                  <jats:italic>Af<\/jats:italic>\n                  invasion.\n                  <jats:italic>In vitro<\/jats:italic>\n                  , iron overload reduced macrophage viability and decreased their capability to kill\n                  <jats:italic>Af<\/jats:italic>\n                  spores, through a decrease in lysosomal acidification and lysosomal loss. Treatment with ferrostatin-1, a ferroptosis inhibitor, and deferasirox (an iron chelator) restored\n                  <jats:italic>Af<\/jats:italic>\n                  killing. Ferroptotic alveolar macrophages isolated from lung transplant patients also showed a decreased ability to kill\n                  <jats:italic>Af<\/jats:italic>\n                  spores and the patients\u2019 bronchoalveolar lavage was characterized by higher iron levels and markers of ferroptotic stress compared to non-lung transplants. These characteristics were strongly correlated with a clinical history of fungal infections, independent of immune suppressive medications. Our findings indicate that macrophage ferroptosis augments the risk of invasive aspergillosis, representing a novel mechanism for host immune dysfunction.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:p>\n                    Schematic of proposed mechanism underlying ferroptosis induced immune dysregulation and increased\n                    <jats:italic>Af<\/jats:italic>\n                    invasion in lung transplantation.\n                  <\/jats:p>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"643092v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.03.13.643092","type":"posted-content","created":{"date-parts":[[2025,3,16]],"date-time":"2025-03-16T04:45:20Z","timestamp":1742100320000},"source":"Crossref","is-referenced-by-count":0,"title":["Macrophage ferroptosis inhibits\n                  <i>Aspergillus<\/i>\n                  conidial killing in lung transplantation"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0907-0203","authenticated-orcid":false,"given":"Efthymia Iliana","family":"Matthaiou","sequence":"first","affiliation":[{"name":"Department of Immunology, Albany Medical Center, Albany, NY, United States of America"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4822-6581","authenticated-orcid":false,"given":"Amer Ali Abd","family":"El-Hafeez","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University School of Medicine, 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