Usp12, a member of the ubiquitin-specific proteases family, is a deubiquitinase. Deubiquitination by Usp12 removes ubiquitin from targeted proteins, maintaining their stability and regulating cellular homeostasis. It is involved in various physiological processes such as cell proliferation, autophagy, apoptosis, and cell cycle progression, and is associated with multiple signaling pathways [1].

Knockout or knockdown of Usp12 has revealed its roles in different biological processes and diseases. In antiviral responses, Usp12 deficiency impairs HSV-1-induced expressions of IFN-β, CCL-5, IL-6, and downstream interferon-stimulated genes (ISGs), increases HSV-1 replication, and host susceptibility to HSV-1 infection, as it normally stabilizes IFI16 through deubiquitination [2]. In lung cancer, downregulation of Usp12 promotes tumor growth, creates an immunosuppressive microenvironment, and desensitizes tumor cells to anti-PD-1 immunotherapy [3]. In gastric cancer, depletion of Usp12 inhibits cancer progression via the Hippo/YAP axis, while overexpression promotes growth by stabilizing YAP [4]. In non-small cell lung cancer, knockdown of Usp12 causes DNA replication stress and retards tumor growth as it deubiquitinates and stabilizes RRM2 [5]. In breast cancer, knockdown of Usp12 decreases lung metastasis ability, as it promotes angiogenesis by maintaining midkine stability [6]. In CD4+ T cells, Usp12-deficient cells protect mice from autoimmune diseases but subdue the immune response against bacterial infection, as Usp12 stabilizes BCL10 and activates the NF-κB signaling pathway [7]. In myeloid-derived suppressor cells (MDSCs), Usp12 deficiency decreases infiltration and impairs the suppressor function of monocytic (M)-MDSCs, accelerating tumor growth [8].

In conclusion, Usp12 plays essential roles in multiple biological processes and diseases. Through gene knockout or knockdown models, its functions in antiviral responses, tumorigenesis, and immune regulation have been elucidated. These findings suggest that Usp12 could be a potential therapeutic target for treating viral infections, cancers, and inflammatory diseases.