Zinc (Zn) is an essential trace element involved in a wide variety of cellular processes and is vital for optimal liver function. Our objective was to elucidate the potential therapeutic role of Zn in hepatocellular carcinoma (HCC), the third leading cause of cancer-related death and the first cause of death in patients with cirrhosis.

The impact of Zn supplementation on proliferation, invasion, migration, cell cycle, and apoptosis was conducted on four HCC cell lines as well as in a xenograft mouse model of HCC from which tumor gene expression profiles were also analyzed. Gene deregulation and protein expression were validated in human HCC tissues. Finally, Zn and MT1 (Metallothionein 1) levels were quantified in plasma from patients with HCC.

Zn supplementation significantly modulated proliferation, invasion, and migration in HCC cell lines and induced apoptosis in a dose-dependent manner. Although Zn did not exhibit a significant increase in survival, Zn supplementation significantly altered the expression of MT genes. Specifically, MT1G and MT1H expression were notably suppressed in HCC tissues from mice and these results were validated in human HCC samples. Overall, gene and protein MTs expression was significantly lower in HCC areas compared to adjacent liver tissue and plasma Zn levels exhibited substantial variation across different stages of the liver disease.

Zn supplementation influences key cellular behaviors in a dose-dependent manner and upregulates the expression of MT family genes, which may have tumor-suppressive properties, in vitro an in vivo models. Future research should investigate the prognostic implications of Zn supplementation as part of a comprehensive therapeutic strategy for HCC patients.