Image 2_MTHFD1L-associated branched-chain amino acid degradation transcriptional signature represents a conserved metabolic program in Epstein-Barr virus-associated malignancies.jpg

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–metabolic pathway pairs across the three discovery cohorts. Among them, only the MTHFD1L—associated 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⁺ T cells, γδ T cells, and NK cells, and was accompanied by cell state-dependent metabolic remodeling, altered cell–cell communication, and distinct MTHFD1L-centered regulatory networks across immune cell populations.