Entinostat suppresses hepatocellular carcinoma metastasis by upregulating AZGP1 through histone acetylation.

Hepatocellular carcinoma (HCC) has a high mortality rate, primarily driven by metastasis. The role of the histone deacetylase inhibitor (HDACi) entinostat in this process remains controversial, limiting its clinical application. This study aims to define entinostat's function and mechanism in HCC metastasis. We employed in vitro models, transcriptomic sequencing, chromatin immunoprecipitation-qPCR, and an orthotopic mouse model to assess the effects of entinostat on epithelial-mesenchymal transition (EMT), invasion, and tumor growth. Our findings demonstrate that entinostat potently prevented and reversed transforming growth factor-β (TGF-β)-induced EMT, suppressing HCC cell invasion and metastasis in vivo without significant toxicity. Transcriptomics identified alpha-2-glycoprotein 1, zinc-binding (AZGP1) as a key target. In addition, entinostat promotes histone H4 acetylation at the AZGP1 promoter, activating its transcription. AZGP1 overexpression mimicked entinostat's effects, while its knockdown largely abolished them. Clinically, high AZGP1 expression was associated with an improved prognosis. In conclusion, our work elucidates a coherent epigenetic pathway wherein entinostat activates AZGP1 to inhibit HCC metastasis. These findings nominate AZGP1 as both a critical mediator and a potential biomarker for entinostat-based therapy in advanced HCC.