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<p>Intrahepatic cholangiocarcinoma (iCCA) is a highly malignant liver cancer with limited treatment options. Recent evidence implicates lactate metabolism as playing a crucial role in tumor progression, but its precise contribution in iCCA remains unclear. In this study, lactate metabolism-related genes (LMRGs) in iCCA were identified through analyses of bulk and single-cell RNA sequencing data, diagnostic models were developed using machine learning algorithms, and the functional significance of candidate genes was validated through a combination of in <i>vitro</i> and in <i>vivo</i> experiments. 38 differentially expressed LMRGs were identified, and two genes, HMGCL and PCK1, were selected as robust diagnostic biomarkers. A nomogram incorporating both markers achieved excellent diagnostic performance (AUC = 0.999). Single-cell analyses revealed cell-type-specific expression and extensive intercellular communication involving these genes. Functional studies demonstrated that PCK1 acts as a tumor suppressor, concurrently reducing lactate accumulation, downregulating protein lactylation, and inhibiting the PI3K-AKT signaling pathway. Overexpressing PCK1 significantly impaired iCCA cell proliferation, migration, and invasion. These results indicate PCK1 is a key lactate metabolism-related tumor suppressor in iCCA. PCK1 exerts its anti-tumor effects by coordinately suppressing lactate accumulation and inhibiting the PI3K-AKT signaling pathway, positioning it as a promising diagnostic biomarker and therapeutic target for iCCA.</p>

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PCK1 attenuates intrahepatic cholangiocarcinoma progression by suppressing lactate accumulation and PI3K-AKT signaling

  • 期刊论文

  • 发表日期：

    2025年12月26日

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  • Yuchen Pei,
  • Weigen Wu,
  • Junlong Wang,
  • Xi Yu,
  • Borui Xu,
  • Zhikang Li,
  • Qianning Li,
  • Xiting Chen,
  • Danhong Zhan,
  • Yao Li,
  • Ruizhi Wang,
  • Jiying Liu,
  • Meifang He,
  • Wei Chen

摘要

Intrahepatic cholangiocarcinoma (iCCA) is a highly malignant liver cancer with limited treatment options. Recent evidence implicates lactate metabolism as playing a crucial role in tumor progression, but its precise contribution in iCCA remains unclear. In this study, lactate metabolism-related genes (LMRGs) in iCCA were identified through analyses of bulk and single-cell RNA sequencing data, diagnostic models were developed using machine learning algorithms, and the functional significance of candidate genes was validated through a combination of in vitro and in vivo experiments. 38 differentially expressed LMRGs were identified, and two genes, HMGCL and PCK1, were selected as robust diagnostic biomarkers. A nomogram incorporating both markers achieved excellent diagnostic performance (AUC = 0.999). Single-cell analyses revealed cell-type-specific expression and extensive intercellular communication involving these genes. Functional studies demonstrated that PCK1 acts as a tumor suppressor, concurrently reducing lactate accumulation, downregulating protein lactylation, and inhibiting the PI3K-AKT signaling pathway. Overexpressing PCK1 significantly impaired iCCA cell proliferation, migration, and invasion. These results indicate PCK1 is a key lactate metabolism-related tumor suppressor in iCCA. PCK1 exerts its anti-tumor effects by coordinately suppressing lactate accumulation and inhibiting the PI3K-AKT signaling pathway, positioning it as a promising diagnostic biomarker and therapeutic target for iCCA.