Usp8, or ubiquitin-specific protease 8, is a deubiquitinase that plays crucial roles in multiple biological processes. It is involved in pathways such as the epidermal growth factor receptor (EGFR) signaling pathway, and its functions are essential for maintaining cellular homeostasis. Genetic models, like knockout (KO) and conditional knockout (CKO) mouse models, are valuable tools for studying its functions [4].

Homozygous deletion of Usp8 in intestinal epithelial cells (IECs) leads to architectural changes in the colonic epithelium, increased IEC death, signs of lipid peroxidation, and shortened mouse lifespan, while heterozygous deletion in IECs makes mice resistant to azoxymethane/dextran sodium sulfate-induced colorectal tumorigenesis. Mechanistically, USP8 interacts with and deubiquitinates glutathione peroxidase 4 (GPX4), stabilizing it, and its inhibition sensitizes cancer cells to ferroptosis in vitro and enhances the efficacy of anti-PD-1 immunotherapy in vivo [1]. In hepatocellular carcinoma (HCC), USP8 depletion decreases β-catenin protein level, inhibits cell proliferation, invasion, and stemness, and confers ferroptosis resistance, while the USP8 inhibitor DUB-IN-3 promotes ferroptosis through β-catenin degradation [2]. Also, targeting USP8 in HCC inhibits proliferation, induces ferroptosis, suppresses tumor growth and lung metastasis by decreasing intracellular cystine levels and glutathione biosynthesis and increasing ROS accumulation [3].

In conclusion, Usp8 is a key deubiquitinase with diverse functions. Through gene knockout mouse models, its roles in processes like ferroptosis, tumorigenesis, and immune-related responses have been revealed. These findings highlight its importance in various disease areas, especially in cancer, suggesting that targeting Usp8 could be a potential therapeutic strategy for enhancing cancer immunotherapy and treating specific cancers [1,2,3].