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Introduction <p>Metabolic steatotic liver disease (MASLD) can progress to hepatocellular carcinoma (HCC). 25% of MASLD-HCCs occur in the absence of fibrosis.</p> Objectives <p>This study aimed to explore lipid metabolic pathways through “omics” and to identify biomarkers of MASLD-HCC based on the degree of fibrosis.</p> Methods <p>Our cohort included 79 pairs of MASLD-HCC tumor tissues (TT) and adjacent non-tumor human liver tissues (NTT), which were divided into two groups according to fibrosis degree (F0F2 <i>n</i> = 45 and F3F4 <i>n</i> = 34). Lipidomic analysis (<i>n</i> = 52) using liquid chromatography high-resolution mass spectrometry (LC-HRMS/MS) and gene expression analysis (<i>n</i> = 79) using RT-qPCR were performed. For each group, TT was compared with NTT. Five healthy liver tissues were used as calibrators in gene expression analysis.</p> Results <p>Using LC-HRMS/MS, 130 lipids were putatively annotated, 30 of which showed a significant difference between TT and NTT. In MASLD-HCC-F0F2, ceramide levels decreased. While sphingomyelin, most phosphatidylcholine and phosphatidylethanolamine species were increased. In contrast, in MASLD-HCC-F3F4, most lipid contents decreased. Based on lipidomic data, a panel of 18 genes related to lipid metabolism was analyzed. The expression of six genes, <i>ACAT2</i>,<i> DGAT2</i>,<i> ACOX1</i>,<i> CHKA</i>,<i> PLD1</i>, and <i>PLD2</i>, was exclusively upregulated in MASLD-HCC-F0F2. Taken together, these data support the existence of two MASLD-HCC lipid metabolic phenotypes, according to the degree of fibrosis.</p> Conclusion <p>In conclusion, our results allow: (1) discriminate two phenotypes of MASLD-HCC according to fibrosis level; (2) propose PLD as a potential drug target for MASLD-HCC-F0F2 patients, and suggest that PLD inhibitor could be evaluated in combination with immunotherapy treatment.</p>

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PLD2 is a marker for MASLD-HCC with early-stage fibrosis: revealed by lipidomic and gene expression analysis

  • 期刊论文

  • 发表日期：

    2025年3月10日

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  • Jihan Sun,
  • Fatima Dahboul,
  • Estelle Pujos-Guillot,
  • Mélanie Petera,
  • Emeline Chu-Van,
  • Benoit Colsch,
  • Delphine Weil,
  • Vincent Di Martino,
  • Aicha Demidem,
  • Armando Abergel

摘要

Introduction

Metabolic steatotic liver disease (MASLD) can progress to hepatocellular carcinoma (HCC). 25% of MASLD-HCCs occur in the absence of fibrosis.

Objectives

This study aimed to explore lipid metabolic pathways through “omics” and to identify biomarkers of MASLD-HCC based on the degree of fibrosis.

Methods

Our cohort included 79 pairs of MASLD-HCC tumor tissues (TT) and adjacent non-tumor human liver tissues (NTT), which were divided into two groups according to fibrosis degree (F0F2 n = 45 and F3F4 n = 34). Lipidomic analysis (n = 52) using liquid chromatography high-resolution mass spectrometry (LC-HRMS/MS) and gene expression analysis (n = 79) using RT-qPCR were performed. For each group, TT was compared with NTT. Five healthy liver tissues were used as calibrators in gene expression analysis.

Results

Using LC-HRMS/MS, 130 lipids were putatively annotated, 30 of which showed a significant difference between TT and NTT. In MASLD-HCC-F0F2, ceramide levels decreased. While sphingomyelin, most phosphatidylcholine and phosphatidylethanolamine species were increased. In contrast, in MASLD-HCC-F3F4, most lipid contents decreased. Based on lipidomic data, a panel of 18 genes related to lipid metabolism was analyzed. The expression of six genes, ACAT2, DGAT2, ACOX1, CHKA, PLD1, and PLD2, was exclusively upregulated in MASLD-HCC-F0F2. Taken together, these data support the existence of two MASLD-HCC lipid metabolic phenotypes, according to the degree of fibrosis.

Conclusion

In conclusion, our results allow: (1) discriminate two phenotypes of MASLD-HCC according to fibrosis level; (2) propose PLD as a potential drug target for MASLD-HCC-F0F2 patients, and suggest that PLD inhibitor could be evaluated in combination with immunotherapy treatment.