Research progress of OTUD7B: from structural function and disease mechanisms to clinical translation.

OTUD7B (Cezanne), a deubiquitinase of the Ovarian Tumor (OTU) domain family, regulates the ubiquitin-proteasome system and plays a role in maintaining cellular homeostasis. Its dysfunction is linked to the pathogenesis of multiple human diseases. In neoplastic diseases, OTUD7B is overexpressed in several solid tumors, including non-small cell lung cancer (NSCLC), gastric cancer, breast cancer, and pancreatic cancer. It promotes tumor cell proliferation, invasion, metastasis, and chemoresistance by stabilizing oncoproteins such as YAP1, ERα, and β-catenin/LEF1. This stabilization activates signaling pathways including NF-κB, Wnt/β-catenin, and Notch. However, its function is context-dependent. In diffuse large B-cell lymphoma (DLBCL), OTUD7B stabilizes TRAF3 to inhibit the non-canonical NF-κB pathway. In hepatocellular carcinoma (HCC), it deubiquitinates and stabilizes p53 to induce apoptosis. In both contexts, high expression correlates with favorable prognosis. In non-neoplastic diseases, OTUD7B also plays a dual role. In experimental autoimmune encephalomyelitis (EAE) models, it protects neurons by deubiquitinating RIPK1 and stabilizing GFAP. This action suppresses inflammation and promotes glial scar formation. Conversely, in pathological cardiac hypertrophy, its role is model-dependent. It protects against ferroptosis by stabilizing HNF4α in pressure-overload models. Under neurohormonal stimulation, it promotes hypertrophy by deubiquitinating SERCA2a and disrupting calcium homeostasis. These findings indicate that OTUD7B is a context-specific regulator. Its expression levels are associated with prognosis in multiple diseases. It shows potential as a diagnostic and prognostic biomarker and as a therapeutic target for specific conditions. This review systematically summarizes the molecular characteristics, expression regulation, physiological functions, and mechanisms of OTUD7B in neoplastic and non-neoplastic diseases. It also discusses the prospects and challenges of its clinical translation.