JOSD2 deubiquitinating enzyme: Structure, function, and potential as a therapeutic target.

BACKGROUND: Ubiquitination, a central post-translational mechanism, shapes the amplitude and duration of cellular signalling. Josephin domain-containing 2 (JOSD2), a Machado-Joseph disease (MJD) family deubiquitinase, eliminates ubiquitin moieties from ubiquitin-conjugated substrates and tunes proteostasis and signalling outputs. Emerging evidence links aberrant JOSD2 activity to diverse pathological states. MAIN BODY: This review, aims to summarize the current data regarding of JOSD2 as a regulatory node in ubiquitin-dependent signalling and discuss the role of its dysregulation in malignancies through interconnected mechanisms, including metabolic rewiring, rewiring of oncogenic signalling circuits, and altered therapeutic responses that promote resistance. Furthermore, the context-dependent roles of JOSD2 beyond cancer emphasized, with reported pathogenic or protective functions in cardiovascular disorders and inflammatory bowel disease. CONCLUSION: The literature highlights JOSD2 as a signalling-relevant deubiquitinase with pleiotropic, context-dependent functions. This review discusses key knowledge gaps-such as incomplete substrate mapping and determinants of tissue specificity-and outlines translational opportunities and challenges for exploiting JOSD2 as a biomarker and therapeutic target.