BAG6 promotes hepatocellular carcinoma growth via enhancing PLK1-mediated aerobic glycolysis.

Bcl-2-associated Athanogene 6 (BAG6) plays critical roles in multiple tumors, but its biological functions and clinical significance in hepatocellular carcinoma (HCC) remain unclear. Multi-omics analyses showed that BAG6 mRNA and protein levels are significantly upregulated in HCC tissues, linked to genetic mutations and aberrant DNA methylation. In the TCGA cohort, BAG6 exhibits high diagnostic accuracy (AUC = 0.935) and is independently associated with poor overall survival (HR = 1.62) and adverse clinicopathological features, as well as correlates with tumor immune microenvironment, tumor mutation burden (TMB), and immunotherapy response. From a public health perspective, its diagnostic value supports integration into machine learning models for early HCC screening to optimize risk stratification, enhance efficiency, and reduce advanced HCC burden. Functional experiments revealed that BAG6 knockdown remarkably inhibits HCC cell growth in vitro and in vivo. BAG6 knockdown decreased PLK1 expression in HCC cells, an essential regulator of the aerobic glycolytic process. Mechanistically, BAG6 directly binds to PLK1 and suppresses its ubiquitination and degradation, and enhances PLK1-mediated Warburg effect, thereby promoting HCC growth. Overall, we identify BAG6 as an HCC progression driver via the PLK1-mediated Warburg effect, a potential therapeutic and early screening marker.