Usp20, or ubiquitin-specific peptidase 20, is a deubiquitylase enzyme. It plays a crucial role in regulating protein stability by removing ubiquitin chains from target proteins, thus influencing various biological pathways. It is involved in processes like cholesterol biosynthesis, reticulophagy, and is associated with multiple disease-related pathways, highlighting its overall biological importance. Genetic models, such as gene knockout mouse models, have been essential in studying its functions [1-4].

In cholesterol biosynthesis, feeding-induced insulin and glucose stimulate mTORC1 to phosphorylate Usp20, which then stabilizes HMGCR, the rate-limiting enzyme in cholesterol synthesis. Mice with liver-specific Usp20 deletion or USP20(S132A/S134A) knock-in show abolished HMGCR stabilization, leading to decreased diet-induced weight gain, reduced lipid levels, improved insulin sensitivity, and increased energy expenditure [1]. In the context of cardiac function, USP20-knockout (KO) mice subjected to pressure overload by transverse aortic constriction (TAC) exhibit severe systolic function deterioration, eccentric cardiac remodeling, increased cardiomyocyte apoptosis, interstitial fibrosis, and higher mortality compared to wild-type mice. This indicates that USP20-dependent signaling suppresses maladaptive remodeling during pressure overload [2].

In conclusion, Usp20 is essential for maintaining protein stability and regulating key biological processes. Gene knockout mouse models have revealed its significance in metabolic diseases like hyperlipidaemia, liver steatosis, obesity, and diabetes, as well as in cardiovascular conditions such as heart failure. Understanding Usp20 functions provides potential therapeutic targets for these disease areas [1,2].