Redox-Active Cerium Oxide Nanoparticles Protect Against Acetaminophen-Induced Acute Liver Injury by Modulating Oxidative Stress and Inflammatory Pathways

Acute liver injury (ALI), often triggered by an acetaminophen (APAP) overdose, is characterized by severe oxidative stress, inflammation, and hepatocyte apoptosis. Current therapies, such as <i>N</i>-acetylcysteine (NAC), are limited by narrow treatment windows, highlighting the need for more effective antioxidant strategies. In this study, cerium oxide nanoparticles (CeO₂ NPs, nanoceria) were synthesized and comprehensively characterized using the transmission electron microscopy (TEM), dynamic light scattering method (DLS), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) to confirm their branched morphology, high crystallinity, and mixed Ce³⁺/Ce⁴⁺ valence states. Their enzyme-mimetic antioxidant activities were evaluated through superoxide, hydrogen peroxide, and hydroxyl radical scavenging assays. Nanoceria exhibited excellent cytocompatibility and effectively suppressed the generation of lipopolysaccharide (LPS)-induced reactive oxygen species (ROS) and lipid peroxidation and caspase-3-mediated apoptosis in macrophages. They also downregulated pro-inflammatory mediators (nitric oxide synthase (iNOS), TNF-α, IL-1β, and NLRP3) while enhancing anti-inflammatory markers (Arg1 and IL-10). In an APAP-induced ALI mouse model, nanoceria preferentially accumulated in the liver, alleviated oxidative stress and inflammation, and significantly reduced aspartate aminotransferase (AST) levels, showing hepatoprotective efficacy comparable to NAC. Nanoceria protect against APAP-induced ALI via synergistic antioxidative and anti-inflammatory mechanisms based on reversible Ce³⁺/Ce⁴⁺ redox cycling. These findings underscore nanoceria's potential as a next-generation nanotherapeutic for oxidative stress-related liver diseases.