USP20 is a deubiquitinating enzyme that regulates multiple cellular processes through stabilization of key proteins. The enzyme plays a central role in cholesterol metabolism by deubiquitinating and stabilizing HMGCR (HMG-CoA reductase), the rate-limiting enzyme in cholesterol biosynthesis, following mTORC1-mediated phosphorylation during feeding states 1. USP20 also maintains ER homeostasis by stabilizing the reticulophagy receptor RETREG1/FAM134B through removal of K48- and K63-linked ubiquitin chains, promoting selective autophagy-mediated ER degradation 2. In cardiac tissue, USP20 protects against pathological hypertrophy through two distinct mechanisms: deubiquitinating STAT3 to reduce its transcriptional activity 3 and stabilizing MYH7 to prevent eccentric remodeling during pressure overload 4. The enzyme demonstrates significant clinical relevance across multiple cancer types, where it is frequently upregulated and associated with poor prognosis 5. In pancreatic cancer, USP20 links inflammatory signaling to metabolic reprogramming and stromal evolution through the STAT3-USP20-HMGCR axis 6, while in bladder cancer it promotes malignancy by stabilizing YAP1 through inhibition of K48-linked polyubiquitination 7. These findings position USP20 as a potential therapeutic target for metabolic diseases and cancer treatment.