FZR1 (fizzy and cell division cycle 20 related 1) functions as a substrate-specific coactivator of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. During late mitosis and G1 phase, FZR1 replaces CDC20 to activate APC/C-mediated ubiquitination of cell cycle regulators, preventing premature accumulation of mitotic drivers 1. FZR1 undergoes phosphorylation-dependent regulation: CDK4/6-mediated phosphorylation at the G1/S transition promotes its dissociation from APC/C 2, while mTOR-mediated phosphorylation during cell cycle entry causes partial APC/C inactivation to facilitate glycolytic metabolism 1. Following DNA damage, FZR1 dephosphorylation restores APC/C activity, enabling ubiquitination of PLK1 and enforcement of the G2 checkpoint. FZR1 also targets RBBP8/CtIP for degradation, influencing DNA repair pathway choice toward NHEJ over homologous recombination. Clinically, FZR1 dysregulation associates with multiple malignancies: reduced FZR1 expression sensitizes B-ALL cells to DNA damage and predicts improved initial remission 3, while elevated FZR1 translation (driven by m6A modification) promotes gemcitabine resistance in pancreatic cancer 4. Additionally, FZR1 loss-of-function variants cause developmental and epileptic encephalopathies with childhood-onset seizures and intellectual disability 5. FZR1 also regulates immune checkpoint signaling by controlling SPOP-mediated PD-L1 degradation 6, offering therapeutic combination opportunities with CDK4/6 and PD-1 inhibitors.