VPREB3 (V-set pre-B cell surrogate light chain 3) is a transmembrane glycoprotein that associates with immunoglobulin mu heavy chains to form the pre-B cell receptor complex in the endoplasmic reticulum 1. During early B cell development, VPREB3 facilitates pre-BCR assembly and regulates pre-B cell expansion and allelic exclusion at the immunoglobulin heavy chain locus 1. Unlike other surrogate light chains, VPREB3 does not traffic to the cell surface but remains ER-resident, where it can bind free immunoglobulin light chains and regulate their maturation and secretion 2. VPREB3 is normally expressed in bone marrow precursor B cells and germinal center B cells 3. In disease contexts, VPREB3 expression is significantly elevated in Burkitt lymphoma (100% of cases) and diffuse large B-cell lymphomas with c-MYC translocations, making it a useful diagnostic biomarker for identifying MYC-translocated lymphomas 3. Combined VPREB3 and ID3 expression shows high sensitivity (0.77) and specificity (0.75) for Burkitt lymphoma diagnosis 4. Emerging evidence suggests non-immunological roles: VPREB3 expression correlates with aldosterone production in adrenocortical adenomas 5, and VPREB3 expression is epigenetically suppressed in diabetic nephropathy through METTL16-mediated m6A methylation, with restoration of VPREB3 alleviating kidney injury 6. VPREB3-derived peptides represent potential targets for TCR-based T cell therapies against B cell malignancies 7.