Usp22, or ubiquitin specific peptidase 22, belongs to the ubiquitin-specific protease (USP) family of deubiquitinases (DUBs). It is involved in regulating ubiquitination, a process crucial in various biological processes such as cell cycle, proliferation, apoptosis, invasion, metastasis, and immunity [6]. By removing ubiquitin chains from substrates, it can change the substrates' biological activity.

In several in vivo studies, Usp22 has shown diverse functions. In hepatocellular carcinoma (HCC), Usp22 promotes tumorigenesis by regulating lipidome accumulation through stabilizing PPARγ [1]. It also promotes hypoxia-induced HCC stemness via a HIF1α/USP22 positive feedback loop upon TP53 inactivation [2]. Additionally, in HCC, the PRDM1-USP22-SPI1 axis regulates PD-L1 levels, leading to CD8+ T cell exhaustion and cancer immune evasion [3]. In colorectal cancer, EZH2 inhibition enhances PD-L1 protein stability through USP22-mediated deubiquitination [4]. In the context of lenvatinib-resistant HCC, the p-MYH9/USP22/HIF-1α axis promotes resistance and cancer stemness [5]. In mice lacking Usp22 in hematopoietic cells, there is profound systemic emergency hematopoiesis, enhancing innate protection against Listeria monocytogenes infection [7]. In human endometrial stromal cells, knockdown of Usp22 reduces cell proliferation and decidualization [8]. In human tumor cell lines, loss of Usp22 expression delays TNFα/Smac mimetic/zVAD.fmk-induced necroptosis [9].

In conclusion, Usp22 plays essential roles in multiple biological processes and disease conditions, especially in cancer-related processes such as tumorigenesis, immune evasion, and drug resistance, as well as in hematopoiesis, cell proliferation, and programmed cell death. Studies using gene knockout or conditional knockout models in mice have been crucial in revealing these functions, providing insights into potential therapeutic targets for related diseases.