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Although bioactive glass nanoparticles (BGNPs) have been extensively studied in regenerative medicine, their direct anticancer potential, particularly against hepatic cancer has not been fully explored. To address this gap, the present study evaluated the therapeutic effects of BGNPs on Hep-G2 hepatic cancer cells, a widely used in vitro model for HCC compared to their impact on viability of normal HFB4 melanocytes. Cell viability was assessed using MTT cytotoxicity assay, while genomic stability was evaluated using the alkaline comet assay. The intracellular reactive oxygen species (ROS) level, mitochondrial membrane potential integrity, and apoptosis induction was also manifested in cancerous Hep-G2 cells to shed more light on BGNP anticancer potential. The results of MTT assay first revealed that BGNPs exhibit strong and selective cytotoxicity toward Hep-G2 hepatic cancer cells with an IC50 value of 72.77\u00a0\u03bcg\/mL, compared to their minimal toxicity exhibited in normal HFB4 melanocytes with an IC50 value of 360.4\u00a0\u03bcg\/mL. This strong targeted cytotoxicity of BGNPs toward Hep-G2 cancer cells was further confirmed by the calculated high selectivity index value of 4.95. Mechanistic studies demonstrated that BGNPs induce substantial (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001) genomic instability, mitochondrial dysfunction, and apoptosis in Hep-G2 cancer cells. These effects were driven by significantly (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001) elevated ROS production, marked (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001) loss of mitochondrial membrane potential, and remarkable dysregulation of critical genes, including significant (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001) upregulation of the pro-apoptotic p53 gene, alongside with marked (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001) downregulation of the anti-apoptotic Bcl-2 gene, and suppression of the ND3 gene involved in mitochondrial respiration. This study provides strong evidence that BGNPs exert selective and targeted cytotoxic effects on Hep-G2 hepatic cancer cells through a multifactorial mechanism involving oxidative stress, mitochondrial disruption, DNA damage, and apoptosis induction. Importantly, BGNPs exhibited minimal toxicity in normal HFB4 melanocytes, suggesting a favorable therapeutic index. To further validate these findings and explore the clinical applicability of BGNPS for hepatocellular carcinoma treatment, future studies including in vivo studies, targeted delivery strategies, and detailed analyses of DNA repair pathways, such as \u03b3-H2AX foci formation and transcriptomic profiling are recommended.\n                  <\/jats:p>","DOI":"10.1007\/s00210-025-04731-6","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T18:39:43Z","timestamp":1762972783000},"page":"5855-5872","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Bioactive glass nanoparticles induce pronounced cytotoxicity in human hepatocellular carcinoma Hep-G2 cells through ROS-mediated genomic instability and mitochondrial apoptosis"],"prefix":"10.1007","volume":"399","author":[{"given":"Hanan R. 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