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

Abstract

Cerium oxide nanoparticles (CeO₂NPs) 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 CeO₂NPs 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 CeO₂NPs 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 CeO₂NPs on cell phosphorylation in human hepatic cells under oxidative stress conditions. CeO₂NPs did not modify HepG2 cell viability in basal conditions but reduced H₂O₂- and lipopolysaccharide (LPS)-induced cell death and prevented H₂O₂-induced overexpression of MPO, PTGS1 and iNOS. Phosphoproteomic analysis showed that CeO₂NPs reverted the H₂O₂-mediated increase in the phosphorylation of peptides related to cellular proliferation, stress response, and gene transcription regulation, and interfered with H₂O₂ effects on mTOR, MAPK/ERK, CK2A1 and PKACA signaling pathways. In conclusion, CeO₂NPs 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.