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Background and Aims  Despite the availability of new‐generation drugs, hepatocellular carcinoma (HCC) is still the third most frequent cause of cancer‐related deaths worldwide. Cerium oxide nanoparticles (CeO 2 NPs) have emerged as an antioxidant agent in experimental liver disease because of their antioxidant, anti‐inflammatory, and antisteatotic properties. In the present study, we aimed to elucidate the potential of CeO 2 NPs as therapeutic agents in HCC.    Approach and Results  HCC was induced in 110 Wistar rats by intraperitoneal administration of diethylnitrosamine for 16 weeks. Animals were treated with vehicle or CeO 2 NPs at weeks 16 and 17. At the eighteenth week, nanoceria biodistribution was assessed by mass spectrometry (MS). The effect of CeO 2 NPs on tumor progression and animal survival was investigated. Hepatic tissue MS‐based phosphoproteomics as well as analysis of principal lipid components were performed. The intracellular uptake of CeO 2 NPs by human  ex vivo  perfused livers and human hepatocytes was analyzed. Nanoceria was mainly accumulated in the liver, where it reduced macrophage infiltration and inflammatory gene expression. Nanoceria treatment increased liver apoptotic activity, while proliferation was attenuated. Phosphoproteomic analysis revealed that CeO 2 NPs affected the phosphorylation of proteins mainly related to cell adhesion and RNA splicing. CeO 2 NPs decreased phosphatidylcholine‐derived arachidonic acid and reverted the HCC‐induced increase of linoleic acid in several lipid components. Furthermore, CeO 2 NPs reduced serum alpha‐protein levels and improved the survival of HCC rats. Nanoceria uptake by  ex vivo  perfused human livers and  in vitro  human hepatocytes was also demonstrated.    Conclusions  These data indicate that CeO 2 NPs partially revert the cellular mechanisms involved in tumor progression and significantly increase survival in HCC rats, suggesting that they could be effective in patients with HCC.

Bespoken Nanoceria: An Effective Treatment in Experimental Hepatocellular Carcinoma