Usp40, a ubiquitin-specific protease, is involved in multiple biological processes. It functions as a deubiquitinase, regulating the stability of various proteins and participating in pathways related to cell survival, proliferation, and tissue integrity. Genetic models, such as knockout (KO) mice, have been crucial in studying its functions [1,2].

In podocyte damage, Usp40 knockout mice showed no abnormal kidney phenotype, but intermediate filament Nestin was upregulated in glomeruli. Usp40 was found to deubiquitinate HINT1, an inducer of p53, and gene knockdown in cultured podocytes reduced HINT1 and p53 protein expression, suggesting its role in the pathological mechanism of podocyte hypertrophy in focal segmental glomerulosclerosis (FSGS) [1]. In zebrafish, Usp40 knockdown disrupted glomerular permeability, indicating its role in glomerulogenesis and glomerular integrity [2]. In endothelial cells, global or EC-targeted depletion of Usp40 in mice exacerbated experimental lung injury, while its lentiviral gene transfer provided protection, suggesting it preserves endothelial integrity [3].

In conclusion, Usp40 plays essential roles in maintaining tissue integrity, such as in the glomeruli and endothelial cells. Through model-based research, especially KO mouse models, its functions in disease-related processes like podocyte hypertrophy in FSGS and endothelial-related lung injury have been revealed. This understanding contributes to a better knowledge of disease mechanisms and potential therapeutic targets.