Usp40, the ubiquitin-specific protease 40, belongs to the deubiquitinase family. It plays a crucial role in multiple biological processes by regulating the ubiquitination status of various proteins, thus affecting associated pathways. Genetic models, such as gene-knockout (KO) mouse models, are valuable for studying its function [1,3].

In podocyte damage, Usp40 knockout mice showed no abnormal kidney phenotype, but an up-regulation of intermediate filament Nestin in glomeruli. Usp40 was found to deubiquitinate HINT1, an inducer of p53, and gene knockdown of Usp40 in cultured podocytes led to reduced HINT1 and p53 protein expression, suggesting its role in the pathological mechanism of podocyte hypertrophy in focal segmental glomerulosclerosis (FSGS) [1]. In zebrafish, knockdown of Usp40 disrupted glomerular permeability, indicating its importance in glomerulogenesis and glomerular integrity [3]. In hepatocellular carcinoma (HCC), Usp40 knockdown inhibited cell proliferation, migration and stemness, while over-expression had the opposite effects, as it interacted with and stabilized Claudin1 by deubiquitination [2]. In endothelial cells, global or endothelial-targeted depletion of Usp40 in mice exacerbated experimental lung injury, and lentiviral gene transfer of Usp40 protected against endotoxin-induced lung injury, showing its role in preserving endothelial integrity [4].

In conclusion, Usp40 is involved in important biological processes such as glomerulogenesis, endothelial integrity maintenance, and is associated with diseases like FSGS and HCC. Studies using KO mouse models have significantly contributed to understanding its role in these disease areas, providing insights into the underlying molecular mechanisms and potential therapeutic targets.