OTUB2 is a cysteine-type deubiquitinase that removes K11-, K48-, and K63-linked polyubiquitin chains from target proteins, preferentially cleaving K63-linked chains [UniProt]. This deubiquitinating activity has emerged as a critical regulator across multiple disease pathways. In cancer, OTUB2 promotes immune evasion by directly interacting with PD-L1 to prevent its ubiquitination and degradation, allowing tumor cells to escape CD8+ T-cell cytotoxicity; pharmacological OTUB2 inhibition reduces PD-L1 levels and suppresses tumor growth 1. OTUB2 also activates oncogenic YAP/TAZ signaling through SUMOylation-dependent mechanisms, promoting cancer stemness and metastasis 2. Conversely, OTUB2 demonstrates disease-promoting roles in neurological and renal pathologies: it stabilizes RIPK3 by removing K48-linked ubiquitin chains, potentiating neuronal necroptosis after ischemic stroke 3, and promotes vascular calcification in chr14 kidney disease via YAP-mediated PFKFB3 transcription 4. In intestinal inflammation, OTUB2 protects against colitis by stabilizing RIPK2, augmenting NOD2-mediated immune signaling 5. Additionally, OTUB2 emerges as an autoantigen in type 1 diabetes, with ERS-induced OTUB2 presentation driving autoreactive CD8+ T-cell responses 6. These findings identify OTUB2 as a therapeutic target with context-dependent effects: inhibition benefits cancer immunotherapy and ischemic stroke, while modulation may address metabolic and inflammatory diseases.