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Background <p>Pyruvate dehydrogenase E1 alpha 1 (PDHA1) is aberrantly expressed in hepatocellular carcinoma (HCC), but its&#xa0;molecular mechanisms in cancer progression remain incompletely understood.</p> Methods <p>Comprehensive gain- and loss-of-function studies were performed in multiple HCC cell lines. RNA&#xa0;immunoprecipitation and molecular analyses were used to identify protein-RNA interactions. In vitro assays&#xa0;measured cell proliferation, migration, and copper-induced cell death resistance. T cell-mediated cytotoxicity and&#xa0;IFNγ secretion were evaluated to assess immune responses.</p> Results <p>PDHA1 was significantly upregulated across multiple HCC cell lines and correlated with poor clinical outcomes. A&#xa0;novel physical interaction between PDHA1 and long non-coding RNA LINC00607 was identified in HCC cells. The&#xa0;PDHA1-LINC00607 complex promoted HCC tumorigenesis through enhanced cell proliferation and migration. PDHA1&#xa0;overexpression conferred resistance to copper-induced cell death (cuproptosis), an effect abolished by LINC00607&#xa0;knockdown. Mechanistic investigations revealed that PDHA1 enhances PD-L1 expression through LINC00607&#xa0;association, facilitating immune evasion. PDHA1 depletion increased T cell-mediated cytotoxicity (50%) and IFNγ&#xa0;secretion (2.3-fold).</p> Conclusion <p>PDHA1 functions as a master regulator in HCC progression through its interaction with LINC00607, simultaneously&#xa0;controlling cuproptosis sensitivity and PD-L1-mediated immune escape. These findings highlight the therapeutic&#xa0;potential of targeting the PDHA1-LINC00607 axis, particularly in combining cuproptosis induction with immune&#xa0;checkpoint blockade.</p>

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PDHA1 Orchestrates Hepatocellular Carcinoma Progression Through LINC00607-Mediated Regulation of Cuproptosis and Immune Evasion

  • 期刊论文

  • 发表日期：

    2025年6月18日

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  • Libai Lu,
  • Yufei Ma,
  • Yuan Lu,
  • Zongjiang Luo,
  • Zhenrong Zhao,
  • Jiasheng Ma,
  • Jianchu Wang

摘要

Background

Pyruvate dehydrogenase E1 alpha 1 (PDHA1) is aberrantly expressed in hepatocellular carcinoma (HCC), but its molecular mechanisms in cancer progression remain incompletely understood.

Methods

Comprehensive gain- and loss-of-function studies were performed in multiple HCC cell lines. RNA immunoprecipitation and molecular analyses were used to identify protein-RNA interactions. In vitro assays measured cell proliferation, migration, and copper-induced cell death resistance. T cell-mediated cytotoxicity and IFNγ secretion were evaluated to assess immune responses.

Results

PDHA1 was significantly upregulated across multiple HCC cell lines and correlated with poor clinical outcomes. A novel physical interaction between PDHA1 and long non-coding RNA LINC00607 was identified in HCC cells. The PDHA1-LINC00607 complex promoted HCC tumorigenesis through enhanced cell proliferation and migration. PDHA1 overexpression conferred resistance to copper-induced cell death (cuproptosis), an effect abolished by LINC00607 knockdown. Mechanistic investigations revealed that PDHA1 enhances PD-L1 expression through LINC00607 association, facilitating immune evasion. PDHA1 depletion increased T cell-mediated cytotoxicity (50%) and IFNγ secretion (2.3-fold).

Conclusion

PDHA1 functions as a master regulator in HCC progression through its interaction with LINC00607, simultaneously controlling cuproptosis sensitivity and PD-L1-mediated immune escape. These findings highlight the therapeutic potential of targeting the PDHA1-LINC00607 axis, particularly in combining cuproptosis induction with immune checkpoint blockade.