Ubiquitin-specific peptidase 33 as a potential therapeutic target for homeostatic dysregulation

Ubiquitination and deubiquitination regulate protein turnover, localization and signaling. Ubiquitin-specific pep-tidase 33 (USP33) participates in these processes through substrates involved in proliferation, apoptosis, migration and treatment response. Its effects differ across malignancies and can diverge within the same tissue. This review examines USP33 structure, upstream regulation and substrate-dependent functions in cancer and other diseases. Comparisons across studies indicate that substrate identity and recruitment, TP53 status, post-translational modifi-cations and cellular environment influence the biological outcome of USP33 activity. We compare biochemical, cellular, animal and patient-associated findings and discuss their implications for inhibitor development, selectivity relative to USP20, targeted degradation and patient selection. No established clinically validated USP33-selective inhibitor is available. Therapeutic development therefore requires compounds with demonstrated target engagement and selectivity, together with evidence that the relevant USP33 pathway can be inhibited without disrupting protective functions in other tissues.