USP4 is a deubiquitinating enzyme that removes conjugated ubiquitin from multiple target proteins, regulating diverse cellular processes with significant disease implications. Mechanistically, USP4 deubiquitinates specific substrates including PDPK1, TRIM21, ADORA2A, HAS2, MAVS, and RHEB to modulate their stability, localization, or signaling activity 123456. USP4 maintains MAVS protein stability to enhance type I interferon production and antiviral immunity 5, and may regulate mRNA splicing through PRPF3 deubiquitination 7. Clinically, USP4 has emerged as a critical regulator in multiple disease contexts. In colorectal cancer, elevated USP4 suppresses antitumor immunity by inhibiting IRF3 activation and cellular interferon responses, contributing to immunotherapy resistance 8. In glioblastoma, USP4 stabilizes ANXA2 through deubiquitination, promoting cancer stem cell maintenance and radioresistance 9. USP4 supports hematopoietic stem cell regeneration and leukemia progression by stabilizing PES1 to enhance ribosome biogenesis and protein synthesis 10. In lung adenocarcinoma, high USP4 expression correlates with increased proliferation and metastasis 11. Additionally, USP4 regulates RAB7A ubiquitination to control autophagy-lysosome fusion, with implications for periodontitis pathogenesis 12, and modulates EPS8 degradation relevant to age-associated neurodegeneration 13. USP4 also ameliorates metabolic disorders including hyperglycemia and non-alcoholic fatty liver disease 14.