USP25, ubiquitin-specific peptidase 25, is a deubiquitinating enzyme that plays crucial roles in various biological processes. It is involved in multiple pathways such as NF-κB, MAPK, and Wnt/β-catenin signaling. Deubiquitination by USP25 can regulate protein function, localization, and degradation, which is essential for maintaining normal cellular homeostasis [1,2,4,5,6]. Gene knockout (KO) and conditional knockout (CKO) mouse models have been valuable in studying its functions.

In KO mouse models, USP25 deficiency has shown significant impacts. In the context of cardiac hypertrophy, USP25-deficient mice had aggravated cardiac hypertrophy and dysfunction under Ang II and transverse aortic constriction treatment, as USP25 normally stabilizes SERCA2a by deubiquitinating it [1]. In cerebral ischemic stroke, USP25-deficient mice had more severe injury, as USP25 normally inhibits microglia-mediated neuroinflammation [2]. In Alzheimer's disease, genetic deletion of Usp25 reduced amyloid deposition, suggesting USP25 promotes amyloid pathology [3]. In hepatocellular carcinoma, knocking out USP25 inhibited tumor growth and distant metastasis in vivo [4]. In male mice with acetaminophen-induced liver injury, inactivation of Usp25 attenuated liver injury [5]. In acute pancreatitis, Usp25-deficient mice had exacerbated pancreatic and lung injury due to up-regulated TBK1-NF-κB signaling in macrophages [7].

In conclusion, USP25 is a key deubiquitinating enzyme with diverse functions. Model-based research, especially through KO mouse models, has revealed its significant roles in diseases like cardiac hypertrophy, cerebral ischemic stroke, Alzheimer's disease, hepatocellular carcinoma, liver injury, and acute pancreatitis. Understanding USP25 provides insights into disease mechanisms and potential therapeutic targets.