Usp39, a spliceosome component and member of the conserved deubiquitylation family, plays diverse essential roles. It is involved in processes like alternative splicing (AS), which increases transcriptome and proteome diversity, and ubiquitin-proteasome dependent proteolysis. It is associated with pathways such as autophagy, PI3K/AKT/HIF-1α, and NF-κB-mediated inflammatory responses, highlighting its importance in maintaining cellular homeostasis and in disease-related processes [1,3,6]. Genetic models, like KO/CKO mouse models, are valuable for studying Usp39's functions.

In mouse models, hepatocyte-specific Usp39 deletion leads to increased lipid accumulation, spontaneous steatosis, and impaired autophagy, revealing its role in hepatic lipid homeostasis [1]. Hepatocyte-specific overexpression of USP39 promotes hepatocarcinogenesis and regulates splice site selection in transgenic mice [2]. Also, in endometrial carcinoma cells, histone lactylation stimulates USP39 expression to promote tumor progression [3]. In HCC, USP39 depletion inhibits cell proliferation and metastasis, and it stabilizes β-catenin and balances ZEB1 ubiquitination with TRIM26 [4,5].

In conclusion, Usp39 is crucial for multiple biological processes. Its study through KO/CKO mouse models has provided insights into diseases such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, hepatocellular carcinoma, and endometrial carcinoma. These findings contribute to understanding disease mechanisms and may lead to new therapeutic strategies targeting Usp39 in these disease areas.