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

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

methodsComprehensive 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.

resultsPDHA1 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).

conclusionPDHA1 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.