BEND3 is a quadruple BEN domain-containing transcriptional repressor with multiple roles in chr6 regulation and gene expression control. Mechanistically, BEND3 functions as a nucleolar repressor that associates with the nucleolar remodeling complex (NoRC) to suppress rDNA transcription 1. SUMOylated BEND3 stabilizes the NoRC component BAZ2A/TIP5 through interactions with the USP21 deubiquitinase 1. Beyond rDNA regulation, BEND3 binds unmethylated promoters and recruits Polycomb repressive complex 2 to establish H3K27me3-mediated silencing of differentiation-associated genes, thereby safeguarding pluripotency 2. BEND3 also enhances chr6 bivalency in developmental contexts 3. In disease contexts, BEND3 expression is significantly elevated in hepatocellular carcinoma (HCC) and correlates with poor clinical prognosis 4. Functionally, elevated BEND3 promotes HCC progression by inducing epithelial-mesenchymal transition and activating the PI3K/AKT/mTOR signaling pathway, thereby enhancing cell proliferation, migration, and invasion 4. Additionally, a surface-exposed BEND3+ T cell subpopulation (~3% of peripheral blood T cells) preferentially produces pro-inflammatory cytokines IL-6 and IL-8 upon TCR stimulation, with increased proportions observed in inflammatory disease patients 5.