Deubiquitinase <scp>USP2</scp> promotes hepatic stellate cell activation via p300 stabilization

Hepatic stellate cell (HSC) activation is a central mechanism in liver fibrosis, with histone acetyltransferase p300 acting as a pivotal transcriptional cofactor. To define upstream regulators of p300 stability during HSC activation, we performed a deubiquitinase inhibitor screen in activated HSCs and identified ubiquitin carboxyl-terminal hydrolase 2 (USP2) as a p300 deubiquitinase. Single-cell RNA sequencing of fibrotic human liver tissues revealed USP2 as the most specifically expressed USP family member in stromal populations, including HSCs, with marked upregulation in chronic liver disease and advanced metabolic dysfunction-associated steatotic liver disease (MASLD). Moreover, we demonstrated that USP2 stabilizes p300 and promotes HSC activation, whereas USP2 knockdown or pharmacological inhibition suppresses p300 accumulation and fibrogenic responses. These findings identify USP2 as a key regulator of p300 stability and HSC activation in liver fibrosis. Impact statement Our study identifies USP2 as a novel regulator of p300 stability and hepatic stellate cell activation, revealing a previously unrecognized mechanism driving liver fibrosis. These findings provide new insight into fibrogenesis and highlight USP2 as a potential therapeutic target, impacting both fundamental biology and translational fibrosis research.