USP29 is a cysteine-type deubiquitinase that plays critical roles in cellular metabolism, immune responses, and disease pathogenesis through K48-linked deubiquitination of key regulatory proteins. In innate immunity, USP29 constitutively interacts with and stabilizes the DNA sensor cGAS by removing K48-linked polyubiquitin chains, promoting type I interferon production and antiviral responses against DNA viruses like HSV-1 1. However, USP29 also facilitates viral pathogenesis by preventing proteasomal degradation of SARS-CoV-2 ORF9b protein, thereby enhancing viral virulence and suppressing host immune responses 2. In cancer biology, USP29 promotes tumorigenesis through multiple mechanisms: it stabilizes the cell cycle regulator CDC25A to drive proliferation 3, coordinates stabilization of metabolic regulators MYC and HIF1α to support tumor metabolism 4, and maintains TWIST1 stability in triple-negative breast cancer when phosphorylated by CDK1, promoting chemoresistance and metastasis 5. Additionally, USP29 regulates metabolic homeostasis by stabilizing ACSL5 to promote fatty acid β-oxidation, protecting against metabolic dysfunction-associated steatotic liver disease 6. Importantly, Usp29 knockout mice are viable with no developmental defects, suggesting USP29 may represent a promising therapeutic target 7.