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However, how EBV regulates B cell mitochondrial function and metabolic fluxes remains unclear. Here, we show that EBV boosts cardiolipin (CL) biosynthesis, essential for mitochondrial cristae biogenesis, via EBV nuclear antigen 2\/MYC-induced CL enzyme transactivation. Pharmacological and CRISPR genetic analyses underscore the essentiality of CL biosynthesis in EBV-transformed B cells. Metabolomic and isotopic tracing highlight CL\u2019s role in sustaining respiration, one-carbon metabolism, and aspartate synthesis. Disrupting CL biosynthesis destabilizes mitochondrial matrix enzymes pivotal to these pathways. We demonstrate EBV-induced CL metabolism as a therapeutic target, offering synthetic lethal strategies against EBV-associated B cell malignancies.<\/jats:p>","DOI":"10.1126\/sciadv.adr8837","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T19:00:04Z","timestamp":1738177204000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":15,"title":["Epstein-Barr virus\u2013driven cardiolipin synthesis sustains metabolic remodeling during B cell transformation"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3041-1826","authenticated-orcid":true,"given":"Haixi","family":"You","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Tufts University, Boston, MA 02111, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4078-1773","authenticated-orcid":true,"given":"Larissa","family":"Havey","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Tufts University, Boston, MA 02111, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8590-875X","authenticated-orcid":true,"given":"Zhixuan","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Brigham and Women\u2019s Hospital, 181 Longwood Avenue, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8137-7496","authenticated-orcid":true,"given":"Yin","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Brigham and Women\u2019s Hospital, 181 Longwood Avenue, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7450-2589","authenticated-orcid":true,"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, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4584-1324","authenticated-orcid":true,"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"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3002878"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1252786"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1001939"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2014.04.004"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2015"},{"key":"e_1_3_2_7_2","unstructured":"E. 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