HDAC inhibitor MS275 reprograms metabolism to induce differentiation and suppress proliferation in hepatocellular carcinoma.

Abstract

Background: Histone deacetylase (HDAC) inhibitors have shown therapeutic promise in various cancers, including hepatocellular carcinoma (HCC), due to their ability to regulate cell proliferation, differentiation, and apoptosis. However, their role in metabolic reprogramming and differentiation therapy in HCC remains underexplored.

Methods: This study investigated the effects of the HDAC inhibitor MS275 on HCC cells in vitro and in vivo. Cell viability, differentiation marker expression, cell cycle distribution, metabolic activity, and reactive oxygen species (ROS) production were evaluated using CCK-8 assays, qRT-PCR, flow cytometry, Seahorse metabolic analysis, and western blotting. A xenograft mouse model was used to validate in vivo efficacy.

Results: MS275 significantly suppressed HCC cell proliferation by inducing G0/G1 phase arrest without triggering apoptosis. MS275 also upregulated hepatocyte-specific markers (GLUL, HNF1A, HNF3A), indicating that it promoted differentiation. Mechanistically, MS275 reprogrammed cellular metabolism by enhancing oxidative phosphorylation and reducing glycolysis, accompanied by increased expression of the metabolic enzyme PKM1. This metabolic shift led to elevated ROS production, which was essential for MS275-induced differentiation. Knockdown of PKM1 abolished both the differentiation and anti-proliferative effects. In vivo, MS275 significantly reduced tumor growth and promoted differentiation without systemic toxicity.

Conclusion: MS275 suppresses HCC cell proliferation and induces hepatocyte-like differentiation through PKM1-mediated metabolic reprogramming and ROS signaling. These findings support the potential of MS275 as a differentiation-based therapeutic strategy for HCC.