GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE336nnn/GSE336950/primary200OKTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE336950GEOGSEfalseEpstein-Barr Virus Induced B cell Methionine Dependency is a Targetable Metabolic VulnerabilityEBV uses latency III oncoproteins to drive abnormal B cell proliferation to establish lifelong latency, and oncoprotein+ B cells correlate to pathology in autoimmune diseases such as systemic lupus erythematosus and multi-sclerosis. EBV-driven B cell outgrowth shows unique features that are different from both cancerous and cytokine-activated B cells, especially in their metabolism. Building on our previous observation that EBV+ tumors depend on methionine for viral epigenetic regulation, we tested whether EBV latency III program B cells share a similar phenotype. Surprisingly, the effect of methionine restriction on latency III cells is distinct and far more drastic—reducing RPMI media methionine level to 10% completely blocked B cell transformation, and to 1% resulted in rapid death of LCL and latency III Burkitt cells. Transcriptomic and liquid chromatography mass spectrometry-based metabolomic analyses revealed that methionine restriction downregulated genes related to the pentose phosphate pathway which supports cystine reduction, and upregulated genes related to ferroptosis, a lipid peroxidation (LPO)-mediated cell death. Isotope-labeled amino acid tracing indicated that methionine was shunt to cysteine biosynthesis pathway. Methionine restriction can be rescued by a combination of quenching LPO (Fer-1 and DFO) and removing toxic cystine buildup (NAC and penicillamine). In mice models, either dietary methionine restriction or injection of engineered methioninase abolished lymphoblastoid cell line tumor growth without having effects on body weight, and refractory tumor cells upregulated pathways against LPO, and downregulated cystine intake, highlighting methionine’s multiple roles in antagonizing LPO and redox pressure via modulating cysteine metabolism. In tonsil organoid model, moderate methionine restriction blocks EBV+ cell outgrowth but did not affect T cell activation and normal germinal center development, implying therapeutic potential. In a B cell transformation assay with a panel of loss-of-function BAC viruses, we identify EBNA2, EBNA-LP, and LMP2A deletion provided protection.2026/07/04GSE336950GSM9845167GSM9845166GSM9845169GSM9845168GSM9845159GSM9845170GSM9845161GSM9845160GSM9845163GSM9845162GSM9845165GSM984516415520336950Homo sapiens