Abrogation of EMP1 Mitigates MASH-Associated Hepatic Fibrosis through Suppression of the JAK/STAT Signaling Axis

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease driven by fibrogenesis, posing high risks for cirrhosis and cancer. Epithelial membrane protein 1 (EMP1) is a biomarker in fibrosis, but its role in MASH is unclear.EMP1 expression was assessed in MASH mouse models (MCD/HFD-induced) and human MASH specimens. The functional effects of EMP1 silencing and overexpression were evaluated in vivo, focusing on steatosis, inflammation, and fibrosis. Mechanistically, the interaction between EMP1 and the JAK/STAT pathway was examined. EMP1 expression was significantly upregulated in both murine MASH models and human MASH liver tissues compared to healthy controls. Functionally, in vivo silencing of EMP1 markedly attenuated hepatic lipid accumulation, inflammatory infiltration, and fibrogenesis in mice fed MCD or HFD. Conversely, EMP1 overexpression exacerbated MASH progression, with a pronounced effect on fibrogenesis. Mechanistic studies demonstrated that EMP1 promotes the phosphorylation of STAT1 and STAT3 via its specific interaction with JAK2, whereas silencing EMP1 disrupts JAK2-mediated activation of downstream signal transducers. This inhibition of the JAK/STAT axis resulted in the suppression of hepatic stellate cell (HSC) activation, a key event in fibrogenesis. Our findings establish EMP1 as a critical pathogenic mediator in MASH-related fibrosis. By directly regulating the JAK2/STAT1/3 signaling axis in HSCs, EMP1 promotes fibrogenesis, highlighting its potential as a novel therapeutic target for the treatment of MASH.