Usp22, or ubiquitin specific peptidase 22, belongs to the ubiquitin-specific protease (USP) family of deubiquitinases (DUBs). Its main function is to remove ubiquitin chains from substrates, thus altering their biological activity. Usp22 is involved in various biological processes, such as immune responses, cell proliferation, and lipid metabolism, and is associated with pathways like autophagy, HIF1α-related signaling, and the regulation of PD-L1 expression [1,2,3,4,5,6,7]. Genetic models, especially KO/CKO mouse models, are valuable for studying its functions.

In KO or knockdown models, Usp22 deficiency leads to increased alum-induced peritonitis and lipopolysaccharide-induced systemic inflammation, as it normally suppresses the NLRP3 inflammasome by promoting NLRP3 degradation via ATG5-dependent autophagy [1]. In hepatocellular carcinoma (HCC) models, down-regulating Usp22 can inhibit tumorigenesis as it promotes lipidome accumulation by stabilizing PPARγ, and also promotes hypoxia-induced HCC stemness through a HIF1α/USP22 positive feedback loop upon TP53 inactivation [2,3]. In colorectal cancer models, knocking down USP22 can enhance the therapeutic efficacy of EZH2 inhibitors, as EZH2 inhibition upregulates USP22 which in turn stabilizes PD-L1 [5]. In addition, Treg-specific ablation of USP22 leads to reduced tumor volume in multiple cancer models, suggesting its role in regulating tumor resistance to immunotherapy [7].

In conclusion, Usp22 plays essential roles in regulating inflammation, tumorigenesis, lipid metabolism, and immune evasion. Studies using KO/CKO mouse models have revealed its significance in NLRP3 inflammasome-related diseases, HCC, and colorectal cancer, providing potential therapeutic targets for these diseases.