OTUD3 is a deubiquitinase that hydrolyzes Lys-6- and Lys-11-linked polyubiquitin chains, including heterotypic and homotypic variants 123. It functions as a metabolic regulator: glucose and fatty acids trigger OTUD3's nuclear translocation through CBP-dependent acetylation, whereupon it deubiquitinates and stabilizes the nuclear receptor PPARD to regulate genes involved in glucose metabolism, lipid metabolism, and oxidative phosphorylation 3. Additionally, OTUD3 negatively regulates ribosome quality control by deubiquitinating 40S ribosomal proteins RPS10 and RPS20, antagonizing ZNF598-mediated ubiquitination 2. Clinically, OTUD3 exhibits context-dependent disease relevance. It functions protectively in ulcerative colitis by deubiquitinating STING in intestinal fibroblasts, suppressing microbiota-mediated inflammation 4, and protects against esophageal cancer by stabilizing ZFP36, which promotes VEGF-C mRNA decay 5. Conversely, OTUD3 is oncogenic in colorectal cancer (promoting YY1 stability), renal cell carcinoma (stabilizing SLC7A11 to suppress ferroptosis), and diffuse large B-cell lymphoma (deubiquitinating PD-L1 and MYL12A) 678. OTUD3 genetic variants associate with type 2 diabetes risk and diabetic retinopathy 9, positioning OTUD3 as both a disease biomarker and potential therapeutic target 1011.