{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:17:14Z","timestamp":1778717834996,"version":"3.51.4"},"posted":{"date-parts":[[2026,1,26]]},"group-title":"Cell Biology","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T00:00:00Z","timestamp":1769385600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"name":"NICHD","award":["R01HD091218-04S1"],"award-info":[{"award-number":["R01HD091218-04S1"]}]},{"name":"NICHD","award":["1R01HD113199-01"],"award-info":[{"award-number":["1R01HD113199-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,26]]},"abstract":"<jats:p>Prenatal SARS CoV 2 infection is associated with adverse pregnancy outcomes, but placental mechanisms that restrict viral spread remain unclear. Here we show that SARS CoV2 exposure induces ferroptosis-linked iron dysregulation in the placenta as a host defense. Human placentas from early gestation SARS CoV 2 exposed pregnancies exhibited persistent viral protein expression at term, iron accumulation, disrupted localization of iron transport proteins, and reduced expression of the ferroptosis inhibitor, GPX4. In trophoblast cells and newly generated stem cell-derived trophoblast organoids (SCTOs) with physiological apical-out polarity, infection with live SARS CoV 2  Delta variant suppressed expression of iron efflux transporter, ferroportin and ferroptosis inhibitors, GPX4 and PLA2G6, promoting lipid peroxidation and ferroptotic signaling. Sub-lethal pharmacological activation of ferroptosis reduced viral titers in trophoblasts, indicating an antiviral function. Together, these results uncover a new mechanism through which the placenta attempts to restrict SARS CoV 2  replication. However, this protective response is accompanied by placental iron sequestration, which may compromise maternal-fetal iron transfer and help explain iron deficiency and anemia reported in infants born after prenatal SARS CoV 2 exposure, highlighting a delicate balance between iron and ferroptosis-mediated protection and damage with implications for pregnancy outcomes.<\/jats:p>","DOI":"10.64898\/2026.01.26.701742","type":"posted-content","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T03:15:11Z","timestamp":1769483711000},"source":"Crossref","is-referenced-by-count":1,"title":["Trophoblast ferroptosis restricts SARS-CoV-2 spread in the placenta"],"prefix":"10.64898","author":[{"given":"Eliza","family":"McColl","sequence":"first","affiliation":[{"name":"Baylor College of Medicine;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deepak U","family":"Kumar","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brittany","family":"Jones","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikole","family":"Marks","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Diveley","sequence":"additional","affiliation":[{"name":"Washington University School of Medicjne;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rowan","family":"Karvas","sequence":"additional","affiliation":[{"name":"CU Anschutz;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thorold","family":"Theunissen","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeannie","family":"Kelly","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3917-8677","authenticated-orcid":false,"given":"Indira U","family":"Mysorekar","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine;"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.01.26.701742","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T03:15:12Z","timestamp":1769483712000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.01.26.701742"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,26]]},"references-count":0,"URL":"https:\/\/doi.org\/10.64898\/2026.01.26.701742","relation":{},"subject":[],"published":{"date-parts":[[2026,1,26]]},"subtype":"preprint"}}