Work

Epithelial membrane protein 1 drives hepatic stellate cell activation via the TLN1/FAK cascade in MASLD donor liver transplantation

Year: 2025

Type: article

Abstract: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has significantly increased, prompting the increased use of steatotic donor livers in transplantation, contributing to a higher incidence and severity of ischemia-reperfusion injury (IRI), necessitating the development of targeted interventions for MASLD-related liver transplantation (MASLD-IRI). Here, we identified epithelial membrane protein 1 (EMP1) as a potential diagnostic and therapeutic target in MASLD-IRI using multi-omics analysis and mechanistic investigations in rodent models and cells, further validating our findings in human samples. Phenotypic observations revealed significant activation of hepatic stellate cells (HSCs) under MASLD-IRI conditions, leading to increased inflammatory liver injury, which correlated with significant upregulation of EMP1 in HSC. Mechanistically, EMP1 upregulation inhibited SMAD-specific E3 ubiquitin-protein ligase 1 (SMURF1)-mediated ubiquitination and degradation of talin1 (TLN1) by competing with SMURF1 for the TLN1 binding site. The subsequent accumulation of TLN1 further promoted phosphorylation of focal adhesion kinase (FAK), establishing a pro-inflammatory signaling axis-EMP1/TLN1/FAK-that amplified HSC activation and aggravated liver injury. Silencing EMP1 suppressed the TLN1/FAK post-translational modification cascade, thereby attenuating HSC activation and downstream inflammation. These findings highlight the potential of EMP1 as a biomarker to monitor the prognosis of MASLD transplantation, as well as a therapeutic target to improve prognosis.

Source: Molecular Biomedicine

DOI: 10.1186/s43556-025-00371-7