Hepatic Usp2 orchestrates de novo lipogenesis through G3bp2 stabilization and β-catenin activation

Abstract The escalating global burden of metabolic diseases including obesity, type 2 diabetes, and metabolic dysfunction-associated fatty liver disease (MAFLD)-highlights an urgent need to identify new therapeutic targets. Although elevated hepatic de novo lipogenesis (DNL) is a hallmark of metabolic dysfunction, targeting its core transcriptional and enzymatic components has proven clinically challenging. Here, using a multi-model comparative transcriptomic strategy, we identify ubiquitin-specific protease 2 (Usp2) as a consistently upregulated gene strongly correlated with steatosis severity. Functional studies demonstrate that Usp2 promotes hepatic lipid accumulation both in vitro and in vivo. Mechanistically, Usp2 directly interacts with the RNA-binding protein G3bp2 and stabilizes it via K63-linked deubiquitination, leading to activation of β-catenin signaling and subsequent upregulation of key lipogenic genes, including Fasn, Scd1, and Plin2. These findings establish the Usp2-G3bp2-β-catenin axis as a previously unrecognized regulatory pathway driving hepatic lipogenesis and nominate Usp2 as a potential therapeutic target in metabolic disease.