Studies have shown that UHRF1 can affect the expression of target genes by regulating DNA methylation, which may be related to the mechanism of cancer cell death, especially ferroptosis. In this study, HuH7 and HepG2 hepatoma cell lines were used. Intracellular GSH/GSSG and NADP+/NADPH levels were assessed to analyze REDOX status, and lipid peroxidation was assessed using lipid peroxidation level assays. The regulation of GSTZ1 by UHRF1 and its modification through DNA methylation were explored. UHRF1 silencing significantly inhibited the growth and reproduction of liver cancer cells, led to iron death in HuH7 and HepG2 cells, and caused REDOX imbalance and lipid peroxidation. Further analysis showed that UHRF1 regulates iron death in liver cancer cells by mediating the expression of GSTZ1. UHRF1 can down-regulate the expression of GSTZ1 through DNA methylation modification. The study revealed that UHRF1 protein inhibits the expression of GSTZ1 by regulating DNA methylation, thereby affecting the iron death of liver cancer cells.