Usp44, a member of the ubiquitin-specific proteases (USPs) family, functions as a deubiquitinase. It participates in multiple biological processes by regulating the deubiquitination of various substrates, influencing pathways related to DNA repair, immune cell function, and cancer-related signaling [5].

In nasopharyngeal carcinoma, Usp44 is hypermethylated and down-regulated. It enhances radiotherapy sensitivity by recruiting and stabilizing TRIM25, which degrades Ku80 and inhibits non-homologous end-joining DNA repair. Knockout of TRIM25 reverses this radiotherapy sensitization effect, suggesting its role in tumor suppression [1].

In regulatory T cells (Tregs), Usp44 promotes Treg function during inflammation by preventing the degradation of FOXP3, an essential transcription factor for Tregs. Tregs lacking Usp44 are less effective in vitro and in vivo [2].

In hepatocellular carcinoma, Usp44 suppresses tumor progression by inhibiting the Hedgehog signaling pathway and PDL1 expression. It interacts with Itch, promoting Itch's deubiquitination and stabilization, leading to Gli1 degradation and inactivation of the pathway [3].

In neuroblastoma, high levels of Usp44 are associated with aggressive disease features. Depletion of the histone H2B ubiquitin ligase subunit RNF20, similar to Usp44 depletion, affects cell proliferation, migration, and invasion, indicating histone H2B as a potential target of Usp44 [4].

In breast cancer, hypermethylation of Usp44 leads to poor expression, and its overexpression suppresses cancer cell proliferation, migration, and invasion [6].

In cholangiocarcinoma, MAD2 interferes with the USP44/LIMA1 complex, promoting cancer progression [7].

In thyroid cancer, Usp44 inactivation accelerates tumor progression by inducing p21 ubiquitylation and degradation [8].

In oral squamous cell carcinoma, Usp44 acts as a tumor suppressor by stabilizing HEXIM1 protein and inhibiting cell proliferation and metastasis [9].

In conclusion, Usp44 plays crucial roles in various biological processes and disease conditions. Through gene knockout or other loss-of-function models in different cancers, it has been revealed that Usp44 can act as a tumor suppressor in many cases, influencing DNA repair, immune cell function, and cancer-related signaling pathways. Understanding Usp44's functions helps in exploring potential therapeutic targets for cancers such as nasopharyngeal carcinoma, hepatocellular carcinoma, and others.