Usp46, a ubiquitin-specific protease, functions as a deubiquitinating enzyme, playing a crucial role in various biological processes. It is involved in pathways such as Wnt/β-catenin signaling, where it forms a complex with UAF1 and WDR20 to deubiquitylate LRP6, promoting Wnt signaling [1,2]. It also participates in processes related to cancer development, antiviral immunity, and synaptic plasticity [3-10]. Genetic models, like knockout or knockdown models in different organisms, are valuable for studying its functions.

In Drosophila, inactivation of Usp46 in Wingless-responding cells destabilizes the receptor Arrow/LRP6, reduces β-catenin accumulation, and disrupts Wingless-dependent developmental patterning [2]. In breast cancer cells, knockdown of USP46 decreases the stability of PTBP1, reduces glycolysis, and heightens tamoxifen sensitivity [3]. In lung cancer, USP46 is downregulated, and its overexpression inhibits cell proliferation by antagonizing PHLPP1 ubiquitination and inhibiting AKT signaling [4]. In hepatocellular carcinoma, overexpression of USP46 impairs cell proliferation and metastasis by stabilizing MST1 and inhibiting YAP1 [5]. In black carp, knockdown of bcUSP46 significantly inhibits the expression of ISG genes and the antiviral activity of host cells [6].

In conclusion, Usp46 is essential for regulating multiple biological processes, especially those related to signaling pathways and cancer-related phenotypes. Model-based research, including KO/CKO-like experiments in different organisms, has revealed its significance in diseases such as breast cancer, lung cancer, and hepatocellular carcinoma, offering potential therapeutic targets for these conditions.