JOSD1 (Josephin domain containing 1) is a deubiquitinating enzyme that plays critical roles in cancer progression, antiviral immunity, and cellular dynamics. The protein functions as a cysteine-type deubiquitinase with unique regulatory properties - its catalytic activity is activated by monoubiquitination, allowing it to cleave both K63-linked and K48-linked polyubiquitin chains 1. JOSD1 preferentially localizes to plasma membranes when ubiquitinated and regulates membrane dynamics, cell motility, and endocytosis by increasing macropinocytosis while suppressing clathrin- and caveolae-mediated endocytosis 1. In cancer contexts, JOSD1 acts as an oncogene by stabilizing anti-apoptotic proteins MCL-1 and Snail through deubiquitination, promoting chemoresistance in gynecological cancers 2 and epithelial-to-mesenchymal transition in lung adenocarcinoma 3. JOSD1 also negatively regulates antiviral immunity by deubiquitinating and stabilizing SOCS1, thereby inhibiting type-I interferon signaling 4. Additionally, JOSD1 can reverse ubiquitination of nucleic acids in vitro 5 and has been identified as a potential pluripotency regulator 6. High JOSD1 expression correlates with poor prognosis in multiple cancers, suggesting its potential as both a therapeutic target and diagnostic biomarker 23.