USP44 is a deubiquitinase that functions as a multifaceted regulator of cellular processes with primary roles in mitotic checkpoint control and DNA damage response. Its canonical function involves stabilizing the spindle assembly checkpoint by mediating CDC20 deubiquitination, thereby preventing premature anaphase onset and maintaining the mitotic checkpoint complex 1. Beyond mitosis, USP44 regulates DNA double-strand break repair by modulating chr12-associated ubiquitin conjugates and participates in nucleotide excision repair through DDB2 deubiquitination. USP44 also stabilizes immune-regulatory proteins, including FOXP3 through K48-linked deubiquitination and STING1 to enhance antiviral immunity 23. Clinically, USP44 functions predominantly as a tumor suppressor across multiple cancer types. In nasopharyngeal carcinoma, USP44 downregulation via promoter hypermethylation correlates with radioresistance; USP44 restoration enhances radiosensitivity by stabilizing TRIM25, which promotes Ku80 degradation and inhibits non-homologous end joining 4. Similarly, in thyroid cancer, USP44 suppresses proliferation by stabilizing the cell cycle inhibitor p21 5. USP44 also inhibits hepatocellular carcinoma progression by stabilizing Itch E3 ligase, inactivating Hedgehog signaling and reducing PDL1 expression 6. However, in gastric cancer, elevated USP44 promotes chemoresistance through ITGB4 stabilization and MAPK/NF-κB pathway activation 7, demonstrating context-dependent roles in treatment response.