USP51 is a deubiquitinating enzyme that plays critical roles in cancer progression and DNA damage response through multiple mechanisms. In DNA repair, USP51 specifically deubiquitinates lysine residues on histone H2A and stabilizes DGCR8, facilitating the recruitment of DNA repair proteins to double-strand breaks 1. However, USP51 is predominantly characterized as an oncogene that promotes tumor progression through the deubiquitination and stabilization of key transcription factors. USP51 directly binds to and deubiquitinates ZEB1, a transcriptional repressor that drives epithelial-mesenchymal transition and metastasis 2. This USP51-ZEB1 axis is regulated by CDK4/6-mediated phosphorylation of USP51, which enhances its deubiquitinase activity 34. Additionally, USP51 promotes cancer stemness by deubiquitinating TWIST1 in non-small cell lung cancer 5 and stabilizes HIF1A through interaction with the VHL E3 ligase complex in colorectal cancer 6. USP51 also contributes to chemotherapy resistance by stabilizing PD-L1 through deubiquitination 78. Clinically, high USP51 expression correlates with poor patient prognosis across multiple cancer types, making it a potential therapeutic target for cancer treatment.