USP2 promotes metabolic dysfunction-associated steatotic liver disease progression via stabilization of PPARγ
- PMID: 40993213
- DOI: 10.1038/s41418-025-01589-2
USP2 promotes metabolic dysfunction-associated steatotic liver disease progression via stabilization of PPARγ
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.
© 2025. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.
Conflict of interest statement
Competing interests: The authors declare no competing interests. Ethics: The collection and use of human samples were approved by the Ethics Committee of Shandong Second Medical University (Approval Number: SDSMU2024YX297) and strictly adhered to the principles of the Declaration of Helsinki. All participants or their close relatives signed written informed consent forms. All animal experiments were conducted with the approval of the Animal Ethics Committee of Shanghai Jiao Tong University School of Medicine (Approval Number: JUMC2023-027-A). All animal experiments were strictly conducted in accordance with institutional guidelines.