Cerium Oxide Nanoparticles Protect against Oxidant Injury and Interfere with Oxidative Mediated Kinase Signaling in Human-Derived Hepatocytes.

Cerium oxide nanoparticles (CeONPs) possess powerful antioxidant properties, thus emerging as a potential therapeutic tool in non-alcoholic fatty liver disease (NAFLD) progression, which is characterized by a high presence of reactive oxygen species (ROS). The aim of this study was to elucidate whether CeONPs can prevent or attenuate oxidant injury in the hepatic human cell line HepG2 and to investigate the mechanisms involved in this phenomenon. The effect of CeONPs on cell viability and ROS scavenging was determined, the differential expression of pro-inflammatory and oxidative stress-related genes was analyzed, and a proteomic analysis was performed to assess the impact of CeONPs on cell phosphorylation in human hepatic cells under oxidative stress conditions. CeONPs did not modify HepG2 cell viability in basal conditions but reduced HO- and lipopolysaccharide (LPS)-induced cell death and prevented HO-induced overexpression of MPO, PTGS1 and iNOS. Phosphoproteomic analysis showed that CeONPs reverted the HO-mediated increase in the phosphorylation of peptides related to cellular proliferation, stress response, and gene transcription regulation, and interfered with HO effects on mTOR, MAPK/ERK, CK2A1 and PKACA signaling pathways. In conclusion, CeONPs protect HepG2 cells from cell-induced oxidative damage, reducing ROS generation and inflammatory gene expression as well as regulation of kinase-driven cell survival pathways.