UCHL1, also known as PGP 9.5, is a multifunctional protein belonging to the deubiquitinase family. It plays crucial roles in regulating cellular free ubiquitin levels, redox state, and the degradation of specific proteins. UCHL1 is highly expressed in neurons of the brain and spinal cord, and is also involved in various biological processes through multiple pathways, such as the Akt/mTOR/HIF-1α pathway [1,4]. It has significance in numerous disease conditions, including neurodegenerative diseases, cancer, and cardiovascular and pulmonary diseases [1-6,8-10]. Genetic models, like knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying its functions.

In pulmonary arterial hypertension (PAH) models, Uchl1 knockout rats (Uchl1-/-) and conditional Uchl1 knockout mice (Tie2Cre-Uchl1fl/fl) showed reduced right ventricular hypertrophy, right ventricular systolic pressures, and obliterative vascular remodeling, suggesting that UCHL1 deficiency attenuates PAH development by reducing AKT1 [2]. In ischemic heart injury studies, cardiomyocytes derived from UCHL1-/-human induced pluripotent stem cells (hiPSCs) were more susceptible to hypoxia/re-oxygenation induced injury, indicating a protective role of UCHL1 via stabilizing HIF-1α [3]. In triple-negative breast cancer (TNBC), UCHL1-silenced cells had different characteristics, with UCHL1 promoting cancer stemness, migration, invasion, and contributing to insensitivity to endocrine therapy by deubiquitinating and stabilizing KLF5 [5,6].

In conclusion, UCHL1 is a key protein involved in multiple biological functions and disease-related processes. The use of Uchl1 KO/CKO mouse models has provided important insights into its role in diseases such as PAH, ischemic heart injury, and TNBC, helping to understand disease mechanisms and identify potential therapeutic targets.