Usp50, also known as ubiquitin specific peptidase 50, is a deubiquitinating enzyme that plays crucial roles in multiple biological processes. It is involved in pathways such as DNA replication, inflammasome activation, and protein stability regulation, which are vital for maintaining cellular homeostasis and normal physiological functions [1-10]. Genetic models, like gene knockout (KO) or conditional knockout (CKO) mouse models, are valuable for studying its functions.

In duodenogastric reflux-induced gastric tumorigenesis, KO of Usp50 reversed bile acid-induced NLRP3 inflammasome activation and HMGB1 release, indicating its role in promoting this process [1]. In DNA replication, depletion of Usp50 led to increased association of DNA2 nuclease and RECQL4 and RECQL5 helicases, causing replication defects, suggesting it suppresses alternative helicase use and deleterious DNA2 activity [2,5]. In LPS-induced sepsis, knocking down Usp50 decreased CPT1a expression and fatty acid oxidation mediated by mitochondrial STAT3 [3]. In tendinopathy, a compound blocked the binding of Usp50 to PYCARD/ASC, reducing its deubiquitination of PYCARD/ASC and alleviating tendinopathy [4]. In SARS-CoV-2 infection, vitamin C blocked the Usp50-ACE2 interaction, promoting ACE2 degradation [7]. In erythropoiesis, overexpression of Usp50 reduced Ku70 protein levels [6]. In the G₂/M checkpoint, depletion of Usp50 caused a loss in Wee1 accumulation [8].

In conclusion, Usp50 is essential in regulating inflammasome activation, DNA replication, protein stability, and metabolic processes. Model-based research, especially KO/CKO mouse models, has revealed its role in diseases such as gastric cancer, sepsis, and tendinopathy, providing insights into disease mechanisms and potential therapeutic targets.