RBL2 (RB transcriptional corepressor like 2) is a pocket protein family member that functions as a key regulator of cell cycle entry and chr16 structure. RBL2 maintains heterochromatin by recruiting histone methyltransferases KMT5B and KMT5C to control histone H4 'Lys-20' trimethylation, thereby mediating epigenetic transcriptional repression 1. It acts as a potent inhibitor of E2F-mediated transactivation, preferentially associating with E2F5 and E4 to repress cell cycle-dependent genes during G0/G1 phases 12. The RBL2-E2F axis also regulates cancer stem cell formation through paracrine WNT signaling mechanisms 2. RBL2 exhibits tumor suppressor activity, with recurrent alterations identified in leiomyosarcoma and Burkitt lymphoma 34. Notably, biallelic loss-of-function RBL2 variants cause Brunet-Wagner neurodevelopmental syndrome, characterized by global developmental delay, intellectual disability, microcephaly, seizures, and white matter abnormalities 5. RBL2 is essential for foregut endoderm differentiation and post-mitotic neuronal function beyond its cell cycle regulatory role 65. Additionally, RBL2 functions as an endogenous CDK2 inhibitor in cardiac tissue, where loss of RBL2 increases sensitivity to anthracycline-induced cardiotoxicity via FOXO1-mediated proapoptotic signaling 7.