RELB is a proto-oncogene encoding an NF-κB transcription factor that functions primarily through the non-canonical NF-κB signaling pathway 1. RELB forms heterodimeric complexes with p50 or p52 that activate target genes, but does not associate with DNA independently or with RELA/p65 [UniProt]. The non-canonical pathway depends on NF-κB-inducing kinase (NIK)-mediated processing of p100 to p52, with RELB stabilization being rate-limiting 1. Mechanistically, RELB regulates diverse cellular processes including lymphocyte development and immune responses 2, circadian rhythm control, and inflammatory gene expression through a negative feedback circuit involving SIX family proteins 3. In disease contexts, RELB contributes to cancer progression: it confers tamoxifen resistance in breast cancer by transcriptionally upregulating GPX4, thereby inhibiting ferroptosis 4; promotes prostate cancer radiation resistance via manganese superoxide dismutase expression 5; and drives cholangiocarcinoma proliferation through the LTβ/NIK/RELB axis 6. RELB also regulates breast cancer stem cell stemness through interaction with nuclear PD-L1 7. Clinically, inherited RELB deficiency causes immunodeficiency characterized by impaired T and B lymphocyte development, failure of B cell differentiation into antibody-secreting cells, and production of autoantibodies against type I interferons, conferring susceptibility to multiple infections 2. Targeting RELB represents a therapeutic strategy in cancer treatment.