CDKN1B (cyclin-dependent kinase inhibitor 1B, also known as p27) is a critical cell cycle regulator that functions as a potent inhibitor of cyclin E-CDK2 and cyclin A-CDK2 complexes, promoting G1 arrest and regulating G1/S phase transition 1. The protein acts as a dual regulator of cyclin D-CDK4 complexes, functioning as either an inhibitor or activator depending on its phosphorylation state and stoichiometry. CDKN1B is subject to ubiquitin-mediated degradation through the Skp2-SCF E3 ligase pathway and other mechanisms 2, which regulates its cellular levels and impact on proliferation control. Clinically, CDKN1B mutations represent a novel tumor susceptibility mechanism. Germline heterozygous mutations in CDKN1B cause multiple endocrine neoplasia type 4 (MEN4), characterized by primary hyperparathyroidism (53.4% risk by age 60), pituitary adenomas (23.2% risk), and neuroendocrine tumors (16.2% risk) 3. Somatic CDKN1B mutations have also been identified in sporadic parathyroid tumors, lymphoma, and breast cancer 4. In cancer progression, CDKN1B loss or degradation promotes tumorigenesis; conversely, CDKN1B stabilization mediates drug-tolerant persister states in breast cancer by restricting polyploidy after mitotic inhibitors 5. Loss of CDKN1B expression correlates with aggressive tumor behavior and poor clinical outcomes across multiple cancer types 2.