Hanan R. H. MohamedRawan EssamBasma A. MohamedGeorge M. HakeemShahd H. ElnawasaniMaria NagyGehan SafwatAyman Diab2025-04-142025-04-142025-04-10Mohamed, H.R.H., Essam, R., Mohamed, B.A. et al. Potent cytotoxicity and induction of ROS-mediated genomic instability, mitochondrial dysfunction, and apoptosis by Y2O3 NPs in Hep-G2 hepatic cancer cells. Naunyn-Schmiedeberg's Arch Pharmacol (2025). https://doi.org/10.1007/s00210-025-04051-9https://doi.org/10.1007/s00210-025-04051-9https://repository.msa.edu.eg/handle/123456789/6378SJR 2024 0.768 Q2 H-Index 101Hepatic cancer, one of the most prevalent and lethal cancers globally, remains a signifcant health challenge, with limited treatment options underscoring the urgent need for novel, more efective therapies. Yttrium oxide nanoparticles (Y2O3 NPs) have attracted attention in nanomedicine due to their promising properties, including enhanced drug delivery, imaging capabilities, and therapeutic efects. However, the specifc impact of Y2O3 NPs on hepatic cancer is largely unexplored. Therefore, this study was conducted to assess the cytotoxic efects of Y2O3 NPs on cell viability, reactive oxygen species (ROS) generation, genomic stability, mitochondrial integrity, and apoptosis induction in Hep-G2 hepatic cancer cells. The results from the SRB cytotoxicity assay demonstrated a strong concentration-dependent decrease in Hep-G2 cell viability, with a notably low half-maximal inhibitory concentration (IC50) value of 13.15 µg/ml. Exposure to the IC50 concentration of Y2O3 NPs led to increased ROS generation, DNA damage induction, and loss of mitochondrial membrane potential. Furthermore, the expression of pro-apoptotic p53 and mitochondrial ND3 genes was signifcantly upregulated, while the anti-apoptotic Bcl-2 gene was markedly downregulated, triggering apoptosis in Hep-G2 cells after 72 h of exposure to Y2O3 NPs. Collectively, these fndings highlight the therapeutic potential of Y2O3 NPs in hepatic cancer, emphasizing the need for further research to fully explore their efcacy as a treatment option for liver canceren-USYttrium oxide nanoparticles · Hepatic cancer · Genomic Instability · Mitochondrial dysfunction and apoptosis inductionArticlehttps://doi.org/10.1007/s00210-025-04051-9