JOSD2 is a cysteine-type deubiquitinase that cleaves Lys-63- and Lys-48-linked polyubiquitin chains to stabilize substrate proteins 1. As a deubiquitinating enzyme, JOSD2 maintains protein homeostasis through substrate deubiquitination and stabilization. In cardiovascular disease, JOSD2 exerts protective effects by stabilizing SERCA2a in cardiomyocytes, improving calcium handling and attenuating angiotensin II-induced cardiac hypertrophy 1. Similarly, JOSD2 stabilizes SMAD7 in vascular smooth muscle cells, inhibiting angiotensin II-induced vascular remodeling via the TGFβ-SMAD pathway 2. In acute kidney injury, JOSD2 deubiquitinates SIRT7 to reduce inflammatory responses and renal tubular injury 3. Conversely, JOSD2 promotes multiple malignancies through substrate stabilization: it stabilizes YAP/TAZ in cholangiocarcinoma 4, KRAS mutants in colorectal cancer via a positive feedback circuit 5, SMAD4 in breast cancer metastasis 6, and inhibits LKB1 tumor suppressor activity in lung cancer 7. Additionally, excessive JOSD2-mediated deubiquitination of NLRP3-R779C variant enhances inflammasome activation, contributing to very-early-onset inflammatory bowel disease 8. These findings establish JOSD2 as a context-dependent regulator with therapeutic potential as a target in cancer and inflammatory conditions, or as a therapeutic agent in cardiovascular disease.