<p>Diffuse Large B-Cell Lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma with heterogeneous molecular characteristics. Altered metabolism, particularly mitochondrial function, has emerged as a critical factor in cancer progression. However, the role of mitochondrial metabolism in DLBCL remains poorly understood. This study aimed to identify key mitochondrial factors associated with DLBCL progression. We analyzed transcriptomic data from multiple DLBCL datasets (GSE83632, TCGA–GTEX, GSE181063, GSE4475) using differential expression analysis, weighted gene co-expression network analysis (WGCNA), and Gene Set Enrichment Analysis (GSEA). The expression and function of the identified key factor, Mitochondrial Pyruvate Carrier 2 (MPC2), were validated using clinical samples, DLBCL cell lines, and an in vivo mouse model of xenograft. Integrative bioinformatics analysis identified MPC2 as a significantly upregulated gene in DLBCL, associated with enrichment of oxidative phosphorylation (OXPHOS) and cell cycle-related genes. MPC2 overexpression was confirmed in clinical DLBCL samples and cell lines at both mRNA and protein levels. Knockdown of MPC2 in DLBCL cells impaired mitochondrial OXPHOS, increased glycolysis, and suppressed cell proliferation, invasion, and 3D spheroid formation. In vivo, MPC2 silencing significantly reduced tumor growth in a xenograft mouse model. Our findings reveal MPC2 as a key regulator of mitochondrial function in DLBCL, promoting tumor progression through enhanced OXPHOS. This study provides new insights into the metabolic reprogramming of DLBCL and suggests MPC2 as a potential therapeutic target for this aggressive lymphoma.</p> Graphical Abstract <p></p>