USP5 is a deubiquitinating enzyme that regulates diverse cellular processes by removing ubiquitin modifications from target proteins. The enzyme stabilizes key oncogenic proteins through deubiquitination, including SLUG in hepatocellular carcinoma by preventing its degradation 1, c-Myc through removal of K48-linked polyubiquitination to promote glucose metabolism reprogramming 2, and PFKP to activate aerobic glycolysis in triple-negative breast cancer 3. USP5 also stabilizes MDH2 via deubiquitination, contributing to ripretinib resistance in gastrointestinal stromal tumors 4. Mechanistically, USP5 activity is regulated by mTORC1-mediated phosphorylation upon insulin stimulation, which promotes enzyme dimerization and enhances its ability to remove K11-linked polyubiquitination from substrates like YTHDF1 5. The enzyme functions downstream of Notch signaling, where it stabilizes STAT3 to enhance pro-angiogenic factor production in esophageal squamous cell carcinoma 6. USP5 also participates in DNA damage response by regulating ATR protein stability through ubiquitination switching from K63- to K48-linked modifications during intervertebral disc degeneration 7. Clinically, USP5 overexpression correlates with poor prognosis across multiple cancer types, making it an attractive therapeutic target.