OTU deubiquitinases as immune-circuit editors: from human immunopathology to therapeutic prioritization.

OTU deubiquitinases are linkage-sensitive ubiquitin editors that regulate immune circuits, human immunopathology, and emerging therapeutic opportunities. By remodeling K48-, K63-, and linear ubiquitin chains, they control protein stability, scaffold assembly, and signal amplitude across nuclear factor κB (NF-κB), and tumor-immune pathways. Individual OTUs have been linked to inflammation, infection, autoimmunity, metabolic dysfunction, and cancer, yet disease-by-disease descriptions often obscure their shared mechanistic logic. We therefore organize current evidence around chain selectivity, substrate context, and immune-circuit function. We examine innate inflammatory regulation, adaptive and tumor immunity, and the emerging therapeutic landscape, including covalent inhibitors, engineered binders, repurposed compounds, and induced-proximity platforms. We also distinguish catalytic from non-catalytic functions, define determinants of context dependence, and propose practical criteria for translational target ranking. This framework positions OTU enzymes not only as an isolated catalogue of disease factors, but also as a mechanistically coherent field centered on mechanism-guided target ranking and disease-specific biological context.