Usp28, a ubiquitin-specific protease, is a catalytically active deubiquitinase that is involved in multiple biological processes. It governs cellular proliferation, DNA damage repair, apoptosis, and oncogenesis. It is associated with pathways like the ubiquitin-proteasome system, mevalonate pathway, and is related to proteins such as PPARα, SREBP2, and ΔNp63, playing a crucial role in maintaining physiological homeostasis [1,2,3]. Genetic models, especially gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying its functions.

In a type 2 diabetes mouse model, cardiac-specific knockout of Usp28 (Myh6-Cre+/Usp28fl/fl in db/db background) led to more severe progressive cardiac dysfunction, lipid accumulation, and mitochondrial disarrangement compared to controls, indicating Usp28's role in suppressing mitochondrial morphofunctional defects and cardiac dysfunction in the diabetic heart [1]. In squamous cancer, silencing of Usp28 reduced the expression of mevalonate pathway enzymes, showing its role in driving tumour growth through controlling SREBP2 [2]. In T-cell acute lymphoblastic leukaemia, genetic depletion of Usp28 strongly destabilized NOTCH1 and inhibited the growth of T-ALL cells [4].

In conclusion, Usp28 is essential in various biological processes, especially in diseases like diabetes-related cardiac dysfunction, squamous cancer, and T-cell acute lymphoblastic leukaemia. The use of KO and CKO mouse models has been instrumental in revealing its role in these disease areas, providing insights into potential therapeutic strategies for these conditions.