ZRANB1 (zinc finger RANBP2-type containing 1) is a multifunctional deubiquitinase with dual enzymatic activities that plays critical roles in cellular homeostasis and cancer biology. As a deubiquitinase, ZRANB1 specifically hydrolyzes K29-linked and K33-linked polyubiquitin chains, with lower efficiency for K63-linked chains 1. The enzyme regulates autophagy through multiple mechanisms, including deubiquitination of UVRAG to inhibit autophagosome maturation and PIK3C3/VPS34 stabilization 1. Notably, ZRANB1 also functions as an E3 ubiquitin ligase, directly ubiquitinating and degrading SLC7A11, a key cystine-glutamate antiporter, thereby promoting ferroptosis by limiting glutathione synthesis 2 3. In cancer contexts, ZRANB1 exhibits tissue-specific roles: it acts as a tumor suppressor in hepatocellular carcinoma by destabilizing oncogenic proteins like Twist1 4, while promoting colorectal cancer progression through Sox9-USP22-Wnt/β-catenin signaling 5. ZRANB1 also stabilizes EZH2 in breast cancer, correlating with poor survival 6. The enzyme's activity is regulated by phosphorylation, and its K33-linked deubiquitinase activity specifically modulates CTSB stability in HBV-related hepatocellular carcinoma 7. These diverse functions position ZRANB1 as a crucial regulator of protein stability with significant therapeutic implications across multiple cancer types.