α-Ketoglutarate mitigates titanium dioxide nanoparticle-induced hepatotoxicity by reinforcing redox balance and PI3K-Akt activation.

The widespread environmental presence of titanium dioxide nanoparticles (TiO2-NPs) has raised growing concern regarding their potential risks to hepatic function and organismal health. This study aimed to systematically elucidate the hepatotoxic mechanisms of TiO2-NPs exposure and to determine whether α-ketoglutarate (α-KG), a central tricarboxylic acid cycle metabolite, could provide metabolic protection. Physicochemical characterization confirmed that the TiO2-NPs exhibited uniform nanoscale morphology, stable hydrodynamic size, defined surface charge, elemental purity, and an anatase crystalline structure. Using a murine exposure model supported by AML12 hepatocyte assays, TiO2-NPs exposure was shown to induce quantitatively measurable, multi-level hepatic injury, including significant suppression of NRF2-dependent antioxidant capacity, attenuation of PI3K-Akt signaling, mitochondrial dysfunction, enhanced inflammatory responses, apoptosis, and early fibrogenic activation. α-KG supplementation significantly mitigated these effects, accompanied by restoration of redox homeostasis and recovery of NRF2 and PI3K-Akt signaling, stabilizing mitochondrial function, and reducing inflammatory and apoptotic injury. These findings demonstrate that α-KG enhances intrinsic metabolic resilience against nanoparticle-induced hepatic toxicity and provide mechanistic and toxicological evidence relevant to environmental nanoparticle risk assessment, highlighting a metabolite-based strategy for mitigating engineered nanomaterial-associated health risks.