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PCK1 deficiency promotes MASH-HCC progression by 12-HETE-induced CD8+ T cell dysfunction.

Kang Wu1, Luo Li2,3, Yi Liu4

  • 1Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.

Gut
|December 17, 2025
PubMed
Summary

Phosphoenolpyruvate carboxykinase 1 (PCK1) is crucial for metabolic dysfunction-associated steatohepatitis-related hepatocellular carcinoma (MASH-HCC) treatment. Restoring PCK1 or inhibiting 12-HETE enhances anti-PD-1 therapy effectiveness against MASH-HCC.

Keywords:
CARCINOGEN METABOLISMFATTY LIVERHEPATOCELLULAR CARCINOMA

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Area of Science:

  • Hepatology
  • Cancer Biology
  • Immunology

Background:

  • Metabolic dysfunction-associated steatohepatitis-related hepatocellular carcinoma (MASH-HCC) shows limited response to immune checkpoint inhibitors.
  • This reduced efficacy may stem from tumor cell metabolic reprogramming and an altered tumor microenvironment.

Purpose of the Study:

  • To investigate the role of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) in MASH-HCC.
  • To explore the interplay between PCK1 and the tumor microenvironment in MASH-HCC.

Main Methods:

  • Established hepatocyte-specific Pten and Pck1 knockout mice to model MASH-HCC.
  • Utilized single-cell RNA sequencing and multiparametrical flow cytometry to analyze immune landscape changes.
  • Performed untargeted metabolomics to identify hepatic metabolism dysregulation.

Main Results:

  • PCK1 was downregulated in MASH-HCC tumor tissues compared to adjacent non-cancerous tissues.
  • Hepatocyte-specific Pck1 knockout mice showed increased tumorigenesis and impaired CD8+ T cell effector function.
  • PCK1 deficiency led to 12-hydroxyeicosatetraenoic acid (12-HETE) accumulation, causing CD8+ T cell dysfunction via the p38 MAPK pathway.
  • Restoring PCK1 or inhibiting 12-HETE, combined with anti-PD-1, enhanced anti-tumor immunity and suppressed MASH-HCC.

Conclusions:

  • Hepatic PCK1 plays a key role in CD8+ T cell dysfunction through 12-HETE-p38 signaling in MASH-HCC.
  • PCK1 represents a potential metabolic target to improve anti-PD-1 immunotherapy efficacy in MASH-HCC.