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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月24日

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  • Tongxi Li,
  • Ran Liu,
  • Huan Cao,
  • Shenghe Deng,
  • Gengqiao Wang,
  • Xueling Wang,
  • Peng Zhao,
  • Xuan Li,
  • Jingjin Zhu,
  • Shuyu Shao,
  • Hao Chen,
  • Lei Liu,
  • Chen Zhang,
  • Chuanzheng Yin,
  • Zifang Song

摘要

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.