By combining computational analyses and animal and cell-based models, we demonstrate that (a) PRDX2 expression is associated with HCC in patients, (b) targeting PRDX2 in hepatocytes prevents HCC development in MASH by improving lipid metabolism and regulating procarcinogenic pathways, and (c) PRDX2 is involved in tumor initiation and progression. This evidence concerns the gene PRDX2 and hepatocellular carcinoma.