Objective：To investigate the expression characteristics of cytochrome B5 reductase 2（NADH-cytochrome B5 reductase 2，CYB5R2）in diffuse large B -cell lymphoma（DLBCL）and its prognostic value，providing new insights for molecular classification and individualized treatment of DLBCL. Methods：This study employed a combined strategy of bioinformatics analysis and clinical validation. First，differentially expressed gene datasets of DLBCL were obtained from the TCGA database，and the DAVID 6.8 platform was used for GO functional enrichment analysis to identify key genes，such as CYB5R2. The differences in expression of CYB5R2 between DLBCL tissues and normal lymphatic tissues were analyzed based on integrated data from the TCGA and GTEx databases. Additionally，a retrospective cohort study was conducted，including 59 DLBCL patients diagnosed pathologically with complete followup data from Jan. 2015 to Dec. 2019 in the First Affiliated Hospital of Nanjing Medical University. Immunohistochemical staining was used to detect CYB5R2 protein expression levels in tumor tissues，and their correlations with clinicopathological features[including Ann Arbor staging，cell of origin（COO）classification，lactate dehydrogenase（LDH）levels，CD10 expression status，etc.]and treatment response[complete response（CR）rate]were analyzed. Kaplan-Meier survival curves were plotted，and survival differences were compared using the Log - rank test. Results：Bioinformatics analysis revealed that CYB5R2 was significantly overexpressed in DLBCL tissues（P ＜0.05）. Clinical cohort validation showed that CYB5R2 expression was higher in cases with elevated LDH levels than those with normal LDH levels（χ² =4.832，P=0.028）. The positive expression rate of CYB5R2 was higher in Non -GCB subtype cases than in GCB subtype cases（χ² =4.468，P=0.035）and higher in CD10-positive cases than in CD10-negative cases（χ² =4.468，P= 0.035）. Survival analysis demonstrated that the 5 - year overall survival（OS）rate of patients with high CYB5R2 expression was significantly lower than that of patients with zero or low CYB5R2 expression（χ² =4.799，P=0.028）. The CR rate in patients with high CYB5R2 expression was significantly lower than that in patients with zero or low CYB5R2 expression（χ² =4.015，P=0.045）. Conclusion：CYB5R2 exhibits a characteristic overexpression pattern in DLBCL，and its overexpression is significantly correlated with adverse prognostic factors such as the Non-GCB subtype and elevated LDH levels. This study provides important theoretical evidence for refining the molecular classification system of DLBCL and developing targeted metabolic therapy strategies.