Usp14, or ubiquitin-specific protease 14, is a deubiquitinating enzyme (DUB) associated with proteasomes. It has a dual function in regulating protein degradation: protecting protein substrates from degradation by removing ubiquitin chains from proteasome-bound substrates and promoting protein degradation by activating the proteasome. It is involved in several canonical signaling pathways and is associated with diseases like cancer, neurodegenerative diseases, autophagy, immune responses, and viral infections [1].

In various disease-related studies, genetic ablation or pharmacological inhibition of Usp14 in mouse models has shown significant effects. In obese mice, genetic ablation or pharmacological inhibition of Usp14 ameliorated hepatosteatosis, hyperglycemia, and insulin resistance as it was found to regulate fatty acid synthase (FASN) stability [3]. In a MC38 syngeneic mouse model, knockdown of Usp14 decreased IDO1 expression, reversed suppression of cytotoxic T cells, and increased responsiveness to anti-PD-1, highlighting its role in colorectal cancer immunotherapy [2]. In middle cerebral artery occlusion (MCAO) mice, inhibition of Usp14 protected BBB integrity, attenuated neuroinflammation, and improved motor function recovery [4]. Also, depletion of Usp14 in pancreatic ductal adenocarcinoma (PDAC) models arrested tumour growth and liver metastasis, and the inhibitor IU1 inhibited PDAC development [5]. In Parkinson's disease female mouse models, Usp14 deficiency improved behavioral abnormities and reduced pathological α-synuclein deposition [6].

In conclusion, Usp14 is a crucial regulator in protein degradation and various biological processes. The use of gene knockout (KO) or conditional knockout (CKO) mouse models has revealed its significant roles in multiple disease areas such as liver diseases, cancer, ischemic stroke, and neurodegenerative diseases. These findings suggest that targeting Usp14 could be a potential therapeutic strategy for treating these diseases.