USP2 promotes metabolic dysfunction-associated steatotic liver disease progression via stabilization of PPARγ.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease worldwide, yet the molecular mechanisms underlying its pathogenesis are not fully understood. Here, we identify the deubiquitinating enzyme Ubiquitin-specific protease 2 (USP2) as a key regulator in hepatic lipid metabolism and MASLD progression. We show that USP2 expression is significantly upregulated in liver tissues from MASLD patients and high-fat diet (HFD)-induced mouse models. Usp2 knockout or pharmacological inhibition alleviates hepatic steatosis and improves systemic metabolic parameters both in vivo and in vitro. Strikingly, hepatocyte-targeted GalNAc-conjugated siRNA against Usp2 markedly attenuates MASLD in mouse models, highlighting therapeutic potential. Mechanistically, USP2 directly interacts with and stabilizes peroxisome proliferator-activated receptor γ (PPARγ) by removing K48-linked ubiquitin chains at lysine 161 within its DNA-binding domain, thereby preventing proteasomal degradation and enhancing its transcriptional activity. This USP2-PPARγ axis promotes hepatic lipid accumulation and drives MASLD progression. Our findings uncover a novel regulatory mechanism in MASLD pathogenesis and suggest that USP2 may represent a promising and druggable therapeutic target for metabolic liver disease.