{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:04:58Z","timestamp":1790831098802,"version":"4.1.0"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>\n                    Epstein-Barr virus (EBV)-associated malignancies encompass multiple tumor types with distinct tissue origins, yet the extent to which they share conserved metabolic programs remains poorly understood. Here, we performed an integrated cross-cancer transcriptomic analysis of nasopharyngeal carcinoma, EBV-associated gastric cancer, and EBV-associated plasmablastic lymphoma to identify conserved metabolic programs, followed by independent cohort validation and single-cell transcriptomic characterization. We identified 103 consensus differentially expressed genes and 72 conserved gene\u2013metabolic pathway pairs across the three discovery cohorts. Among them, only the MTHFD1L\u2014associated Valine, leucine and isoleucine degradation program was consistently preserved in both the discovery and validation cohorts. Single-cell analysis further demonstrated that this conserved metabolic program was predominantly enriched in CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells, \u03b3\u03b4 T cells, and NK cells, and was accompanied by cell state-dependent metabolic remodeling, altered cell\u2013cell communication, and distinct MTHFD1L-centered regulatory networks across immune cell populations. Collectively, our study identifies an MTHFD1L-associated branched-chain amino acid degradation transcriptional co-expression signature as a conserved metabolic program shared across EBV-associated malignancies and reveals its immune cell-specific and dynamic characteristics. These findings provide new insight into the metabolic adaptation of EBV-associated malignancies and offer a conceptual framework for the development of metabolism-targeted therapeutic strategies for virus-associated cancers.\n                  <\/jats:p>","DOI":"10.3389\/fcimb.2026.1955009","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:50:29Z","timestamp":1790830229000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["MTHFD1L-associated branched-chain amino acid degradation transcriptional signature represents a conserved metabolic program in Epstein-Barr virus-associated malignancies"],"prefix":"10.3389","volume":"16","author":[{"given":"Jianmei","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine","place":["Shiyan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hu","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine","place":["Shiyan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxia","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, Shandong Second Medical University","place":["Weifang, China"]},{"name":"Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine","place":["Shiyan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoran","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, Shandong Second Medical University","place":["Weifang, China"]},{"name":"Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.2505","article-title":"Virus-induced host cell metabolic alteration","volume":"34","author":"Bappy","year":"2024","journal-title":"Rev. Med. Virol."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1010254","article-title":"Epstein-Barr virus oncoprotein-driven B cell metabolism remodeling","volume":"18","author":"Burton","year":"2022","journal-title":"PloS Pathog."},{"key":"B13","doi-asserted-by":"publisher","first-page":"9","DOI":"10.32604\/or.2025.071152","article-title":"Branched-chain amino acid metabolic reprogramming and cancer: Molecular mechanisms, immune regulation, and precision targeting","volume":"34","author":"Cai","year":"2025","journal-title":"Oncol. Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1016\/j.chembiol.2024.02.001","article-title":"Metabolic rewiring and communication in cancer immunity","volume":"31","author":"Chapman","year":"2024","journal-title":"Cell Chem. Biol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1552","DOI":"10.1038\/s12276-024-01263-6","article-title":"The role of BCAA metabolism in metabolic health and disease","volume":"56","author":"Choi","year":"2024","journal-title":"Exp. Mol. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1038\/s41576-021-00444-7","article-title":"Temporal modelling using single-cell transcriptomics","volume":"23","author":"Ding","year":"2022","journal-title":"Nat. Rev. Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.cmet.2016.08.009","article-title":"One-carbon metabolism in health and disease","volume":"25","author":"Ducker","year":"2017","journal-title":"Cell Metab."},{"key":"B21","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/s42255-020-00317-z","article-title":"Metabolites and the tumour microenvironment: From cellular mechanisms to systemic metabolism","volume":"3","author":"Elia","year":"2021","journal-title":"Nat. Metab."},{"key":"B16","doi-asserted-by":"publisher","first-page":"3334","DOI":"10.3390\/ijms27073334","article-title":"Integration of bulk and single-cell RNA sequencing analyses in biomedicine","volume":"27","author":"Golushko","year":"2026","journal-title":"Int. J. Mol. Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1574","DOI":"10.1038\/s41556-022-01002-x","article-title":"Metabolic communication in the tumour-immune microenvironment","volume":"24","author":"Kao","year":"2022","journal-title":"Nat. Cell Biol."},{"key":"B1","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1002\/ijc.35192","article-title":"Metabolic regulation of the tumour and its microenvironment: The role of Epstein-Barr virus","volume":"156","author":"Lee","year":"2025","journal-title":"Int. J. Cancer"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1856","DOI":"10.1172\/jci90253","article-title":"Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma","volume":"127","author":"Lee","year":"2017","journal-title":"J. Clin. Invest."},{"key":"B18","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1038\/s41568-020-0273-y","article-title":"Metabolism of immune cells in cancer","volume":"20","author":"Leone","year":"2020","journal-title":"Nat. Rev. Cancer"},{"key":"B7","doi-asserted-by":"publisher","first-page":"3412","DOI":"10.3390\/cancers15133412","article-title":"Targeting metabolic vulnerabilities in Epstein-Barr virus-driven proliferative diseases","volume":"15","author":"Leung","year":"2023","journal-title":"Cancers (Basel)"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.70153","article-title":"Beyond the usual suspects: Emerging associations between Epstein-Barr virus infection\/infectious mononucleosis and cancers","volume":"36","author":"Muckian","year":"2026","journal-title":"Rev. Med. Virol."},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.70798","article-title":"Epstein-Barr virus-associated T\/NK-cell neoplasms","volume":"98","author":"Sato","year":"2026","journal-title":"J. Med. Virol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1007\/s00432-021-03824-y","article-title":"Estimating the global burden of Epstein-Barr virus-related cancers","volume":"148","author":"Wong","year":"2022","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1186\/s12967-025-06664-3","article-title":"Branched-chain amino acid and cancer: Metabolism, immune microenvironment and therapeutic targets","volume":"23","author":"Xiong","year":"2025","journal-title":"J. Transl. Med."},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.22541\/au.173407685.59785736\/v1","article-title":"Metabolic reprogramming in Epstein-Barr virus associated diseases","volume":"97","author":"Yee","year":"2025","journal-title":"J. Med. Virol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1038\/nrc.2016.92","article-title":"Epstein-Barr virus: More than 50 years old and still providing surprises","volume":"16","author":"Young","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.02168-16","article-title":"Epstein-Barr virus-encoded latent membrane protein 1 upregulates glucose transporter 1 transcription via the mTORC1\/NF-\u03baB signaling pathways","volume":"91","author":"Zhang","year":"2017","journal-title":"J. Virol."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2026.1955009\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:50:38Z","timestamp":1790830238000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2026.1955009\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":21,"alternative-id":["10.3389\/fcimb.2026.1955009"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2026.1955009","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]},"article-number":"1955009"}}