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We previously reported that EBV latency oncogene programs dynamically remodel infected B cell metabolism and sensitivity to induction of ferroptosis, a programmed cell death pathway driven by lipid reactive oxygen species. However, much has remained unknown about how EBV remodels key redox defense pathways in support of infected B cell proliferation. Here, we identify EBV latent membrane protein 1 (LMP1), a key viral oncogene necessary for B cell immortalization and which mimics aspects of CD40 signaling, drives resistance to ferroptosis induction by erastin, a small molecule that blocks cystine uptake. LMP1 expression was sufficient to protect Burkitt cells from erastin ferroptosis induction. Mechanistically, signaling from the LMP1 TES2\/CTAR2 region drove this phenotype, which was not shared by CD40 signaling, revealing that LMP1 evolved independent redox defense roles. Metabolomic analysis highlighted key LMP1 and TES2 signaling roles in support of antioxidant cysteine and glutathione levels. TES2 signaling supported cystine uptake, glutathione and NADPH pools in newly infected peripheral blood B cells. We identified PFKFB4, a host enzyme that shunts glucose into the pentose phosphate pathway to support NADPH production, as a major TES2 metabolic target. PFKFB4 knockdown increased EBV-transformed lymphoblastoid cell line lipid ROS levels, decreased glutathione and strongly sensitized them to ferroptosis induction by erastin treatment. PFKFB4 was also necessary for LMP1-mediated Burkitt B cell ferroptosis resistance. Collectively, these results identify PFKFB4 as a key host cell EBV metabolism remodeling target critical for infected B cell redox defense.<\/jats:p>","DOI":"10.64898\/2026.03.09.710628","type":"posted-content","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T02:55:27Z","timestamp":1773197727000},"source":"Crossref","is-referenced-by-count":2,"title":["Epstein-Barr Virus Latent Membrane Protein 1 Suppresses Ferroptosis via Pentose Phosphate Pathway and Glutathione Metabolism"],"prefix":"10.64898","author":[{"given":"Eric M.","family":"Burton","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts, United States of America"},{"name":"Center for Integrated Solutions for Infectious Diseases, Broad Institute, Cambridge, Massachusetts, United States of America"},{"name":"Department of Microbiology, Harvard Medical School, Boston, Massachusetts, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bidisha","family":"Mitra","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts, United States of America"},{"name":"Center for Integrated Solutions for Infectious Diseases, Broad Institute, Cambridge, Massachusetts, United States of America"},{"name":"Department of Microbiology, Harvard Medical School, Boston, Massachusetts, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Tufts University, Boston, MA 02111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Asara","sequence":"additional","affiliation":[{"name":"Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin E.","family":"Gewurz","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts, United States of America"},{"name":"Center for Integrated Solutions for Infectious Diseases, Broad Institute, Cambridge, Massachusetts, United States of America"},{"name":"Department of Microbiology, Harvard Medical School, Boston, Massachusetts, United States of America"},{"name":"Harvard Program in Virology, Harvard Medical School, Boston, Massachusetts, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026031211100859000_2026.03.09.710628v1.1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/130.2.187"},{"key":"2026031211100859000_2026.03.09.710628v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(64)91524-7"},{"key":"2026031211100859000_2026.03.09.710628v1.3","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-10-5765-6_5"},{"key":"2026031211100859000_2026.03.09.710628v1.4","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16206"},{"key":"2026031211100859000_2026.03.09.710628v1.5","doi-asserted-by":"publisher","DOI":"10.30560\/mhs.v2n1p1"},{"key":"2026031211100859000_2026.03.09.710628v1.6","doi-asserted-by":"crossref","unstructured":"A. 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