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

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.