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Calcium titanate nanoparticles (CaTiO\n                    <jats:sub>3<\/jats:sub>\n                    NPs) have previously demonstrated significant cytotoxic effects against MCF-7 breast cancer and A549 non-small cell lung cancer lines. However, their therapeutic potential against tongue cancer remains unexplored. Therefore, this study investigates, for the first time, the cytotoxic effect of CaTiO\n                    <jats:sub>3<\/jats:sub>\n                    NPs on HNO-97 tongue cancer cells in comparison to normal human skin fibroblasts (HSF) cells. Using various assays, we assessed their effects on cell viability, reactive oxygen species (ROS) generation, genomic DNA and mitochondrial integrity, and cell death pathways. Cytotoxicity assessment using the sulforhodamine B (SRB) assay demonstrated that CaTiO\n                    <jats:sub>3<\/jats:sub>\n                    NPs significantly reduced HNO-97 cell viability in a concentration-dependent manner, with an IC50 of 29.67\u202f\u00b5g\/ml. In contrast, normal HSF cells exhibited a much higher IC50 of 262.6\u202f\u00b5g\/ml, indicating strong selectivity for cancer cells (selectivity index\u2009=\u20098.85). Mechanistic studies revealed that HNO-97 cell exposure CaTiO\n                    <jats:sub>3<\/jats:sub>\n                    NPs at the IC50 concentration markedly increased ROS production, inducing oxidative stress. This led to significant genomic DNA damage, confirmed by the comet assay, and mitochondrial dysfunction, validated through Rhodamine-123 staining. Flow cytometry analysis indicated the induction of both apoptotic and necrotic pathways. At the molecular level, qRT-PCR analysis revealed significant downregulation of key genes, including the pro-apoptotic\n                    <jats:italic>p53<\/jats:italic>\n                    , the anti-apoptotic\n                    <jats:italic>Bcl-2<\/jats:italic>\n                    , and the mitochondrial\n                    <jats:italic>ND3<\/jats:italic>\n                    gene, supporting the involvement of mitochondrial dysfunction and impaired DNA repair mechanisms in the observed cytotoxic effects. Conclusion: Collectively, these findings demonstrate that CaTiO\n                    <jats:sub>3<\/jats:sub>\n                    NPs elicit strong and selective multi-modal cytotoxic effects against HNO-97 tongue cancer cells and minimal impact on normal HSF cells, supporting their promise as a novel nanotherapeutic agent for tongue cancer. Further in vivo studies are needed to validate their therapeutic efficacy, clinical applicability and biosafety.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical abstract<\/jats:bold>\n                  <\/jats:p>\n                  <jats:p>\n                    Mechanistic pathway of CaTiO\n                    <jats:sub>3<\/jats:sub>\n                    NPs induced cytotoxicity in HON-97 tongue cancer cells\n                  <\/jats:p>","DOI":"10.1007\/s00210-025-04323-4","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T06:40:19Z","timestamp":1749019219000},"page":"17121-17133","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Induction of potent preferential cell death, severe DNA damage and p53-independent ROS-mediated mitochondrial apoptosis by CaTiO3NPs in HNO-97 tongue cancer cells"],"prefix":"10.1007","volume":"398","author":[{"given":"Hanan R. 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