USP13 ameliorates metabolic dysfunction-associated steatohepatitis through targeting PTEN.

Objective: The role of ubiquitin-specific protease 13 (USP13) in metabolic dysfunction-associated steatohepatitis (MASH) remains unclear. This study aimed to elucidate the role of USP13 in MASH progression.

Methods: THLE-2 cells were subjected to palmitate acid (PA) to generate an in vitro model of lipid accumulation and inflammation. Two in vivo models of MASH were established by feeding mice with a high-fat, high-fructose and high-cholesterol (HFFC) diet for 16 weeks and a methionine/choline-deficient diet (MCD) for 4 weeks, respectively. Usp13 overexpression and knockout (KO) techniques were employed to investigate its role in MASH.

Results: USP13 expression was significantly downregulated in the livers of MASH mice and in the in vitro model of lipid accumulation and inflammation. Hepatic overexpression of Usp13 markedly alleviated liver steatosis, inflammation and fibrosis, while knockout of Usp13 exacerbated the MASH phenotype. Mechanistically, USP13 directly bound to phosphatase and tensin homolog (PTEN) and deubiquitinated it, thereby elevating the PTEN expression and improving the MASH phenotype. Notably, Pten overexpression in Usp13 knockout mice reversed the exacerbation of MASH brought from Usp13 deficiency.

Conclusions: Our findings revealed that USP13 alleviates MASH by directly binding to and deubiquitinating PTEN. The USP13-PTEN axis may represent a promising molecular target for MASH treatment.