ArticleCell death and differentiation2026
USP2 promotes metabolic dysfunction-associated steatotic liver disease progression via stabilization of PPARγ.
Article in Cell death and differentiation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Ubiquitin-Specific Protease 2 (USP2) as a Modulator of Energy Metabolism: A Review of Studies Using Animal and Cellular Models.Biomedicines · 2026Review
- Ubiquitination modifications as central regulators of metabolic dysfunction in type 2 diabetes mellitus.Frontiers in endocrinology · 2026Review
- Post-translational modifications in hepatocellular carcinoma: mechanisms and therapeutic potential.Medical oncology (Northwood, London, England) · 2025Review
- Sucrose but not arsenic induce hepatic steatosis which correlates with calpain-1 inhibition.PloS one · 2025Article
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19 authors.
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Abstract
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.
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