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Methods: HepG2 cells were chronically exposed (~16 weeks) to low doses (1.5 µg/mL) of aged or fresh ZnO NPs. RNA sequencing identified transcriptomic changes (n=3/group); migration and invasion assays assessed function, and a TF-mRNA network was built with clinical survival correlation. Results: Aged ZnO NPs activated pro-oncogenic pathways (e.g., JAK-STAT), increasing migration/invasion and implicating CEBPA, CTNNB1, and STAT3 in worse survival. Conclusion: Chronic exposure may promote a more aggressive phenotype via oncogenic pathway modulation and a transcriptional network linked to poor outcomes.",{"@graph":69,"@context":126},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/rna-sequencing-explores-potential-mechanisms-underlying-the-enhanced-aggressive-phenotype-of-hepg2-cells-induced-by-aged-zinc-oxide-nanoparticles/351689/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/rna-sequencing-explores-potential-mechanisms-underlying-the-enhanced-aggressive-phenotype-of-hepg2-cells-induced-by-aged-zinc-oxide-nanoparticles/351689.png","ImageObject",300,407,{"name":92,"@type":93},"Adam","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-23","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":8},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118,122],{"name":109,"@type":110,"acceptedAnswer":111},"What was the study’s main goal?","Question",{"text":112,"@type":113},"To determine whether environmentally aged ZnO nanoparticles produce different long-term effects than fresh ZnO nanoparticles on an enhanced aggressive phenotype in HepG2 hepatocellular carcinoma cells.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How were HepG2 cells exposed and what was measured?",{"text":117,"@type":113},"Cells were chronically exposed for about 16 weeks to low-dose aged or fresh ZnO NPs (1.5 µg/mL). RNA sequencing identified transcriptomic changes, and migration/invasion assays evaluated functional outcomes.",{"name":119,"@type":110,"acceptedAnswer":120},"Which molecular pathways and regulators were implicated by the results?",{"text":121,"@type":113},"Aged ZnO NPs activated pro-oncogenic pathways such as JAK-STAT and increased cell migration and invasion. Network analysis suggested CEBPA, CTNNB1, and STAT3 as potential core transcriptional regulators.",{"name":123,"@type":110,"acceptedAnswer":124},"What does the conclusion suggest about risk assessment?",{"text":125,"@type":113},"Even with lower acute toxicity, chronic exposure to environmentally aged ZnO NPs may promote a more aggressive liver-cell phenotype, suggesting that environmental aging should be considered in nanomaterial risk assessment.","https://schema.org",{"og:url":83,"og:type":128,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":130,"canonical":83},"index,follow",{"doc_id":132,"site_id":62},351689,1790160656,{"code":4,"msg":5,"data":135},{"doc_id":132,"user_id":136,"nickname":92,"user_avatar":137,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":138,"file_id":139,"file_url":140,"file_type":141,"file_size":142,"view_count":8,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":143,"language":144,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":145,"faqs":146,"seo_title":147,"seo_description":67,"update_tm":148,"read_time":149},1374404737137,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","International Journal of Nanomedicine  \n Open Access Full Text Article  \nORIGINAL RESEARCH  \nRNA Sequencing Explores Potential Mechanisms Underlying the Enhanced Aggressive Phenotype of HepG2 Cells Induced by Aged Zinc Oxide Nanoparticles  \nJin Xu, Na Yu, Jingya Yang, Siyu Wang , Tong Lin, Meimei Wang  \nDepartment of Pathophysiology, School of Basic Medical Science, Anhui Medical University, Hefei, Anhui, 230032, People’s Republic of China Correspondence: Meimei Wang, [Email wangmm1218@ahmu.edu.cn](Email wangmm1218@ahmu.edu.cn)  \n\n| Purpose: While aged zinc oxide nanoparticles (ZnO NPs) show reduced acute cytotoxicity, their chronic effects remain unclear. This study compared the long-term, low-dose impact of environmentally aged versus fresh ZnO NPs on enhanced aggressive phenotype in hepatocellular carcinoma cells.\u003Cbr>Material and Methods: HepG2 cells were chronically exposed (approximately 16 weeks) to low doses (1.5 µg/mL) of aged or fresh ZnONPs. RNA sequencing (n=3 per group) identified transcriptomic changes, while migration and invasion assays validated functional outcomes. A transcription factor (TF) -mRNA network was constructed, and clinical correlation was analyzed using patient survival data. Results: Aged ZnO NPs were associated with the activation of pro-oncogenic pathways (e.g. JAK-STAT) and induced increased cell migration and invasion compared to fresh NPs. Network analysis suggested CEBPA, CTNNB1, and STAT3 as potential core transcriptional regulators. Consistent with their potential role in promoting an aggressive phenotype, the elevated expression levels of these TFs were associated with reduced overall survival in patients with hepatocellular carcinoma.\u003Cbr>Conclusion: Chronic exposure to environmentally aged ZnO NPs, despite lower acute toxicity, may promote a more aggressive phenotype in liver cells compared to fresh NPs. This effect is potentially mediated by the specific modulation of oncogenic pathways and a core transcriptional network linked to poor patient outcomes. Our findings suggest that the environmental aging process could bean important factor influencing the long-term potential of ZnO NPs to promote an aggressive phenotype, which should be considered in nanomaterial risk assessment.\u003Cbr>Keywords: zinc oxide nanoparticles, aging, HepG2 cells, transcriptomics, enhanced aggressive phenotype |\n| --- |\n| Introduction\u003Cbr>The widespread application of engineered nanomaterials, particularly zinc oxide nanoparticles (ZnO NPs), in consumer products, agriculture, and biomedicine has led to their increasing environmental release, 1–3 raising concerns about potential human health risks.4,5 For instance, acute exposure to ZnO NPs has been observed to induce increased airway resistance, hyperinflammatory response, and histological damage in rat lungs, while in vitro studies demonstrate the induction of ROS production, decrease in mitochondrial membrane potential, and activation of the NLRP3 inflammasome in A549 cells.6 Furthermore, Qin et al reported that ZnO NPs can induce ferroptosis in HUVECs and EA.hy926 cells, with elevated intracellular iron levels and lipid peroxidation in a dose-and time-dependent manner.7 Similarly, Valdiglesias et al discovered that ZnO NPs induce considerable cytotoxicity in glial cells, including decreased viability and cytoskeletal alterations, also following dose-and time-dependent kinetics.8\u003Cbr>The hepatotoxicity induced by ZnONPs, as evidenced by the accumulation of experimental data, underscores the liver’s role as a primary target organ for NPs accumulation.9, 10 Given this specific susceptibility and the substantial global burden of hepatocellular carcinoma (HCC)–which ranks as the sixth most common malignancy worldwide and the third leading cause of |\n\n[https://doi.org/10.2147/IJN.S604287](https://doi.org/10.2147/IJN.S604287)  \n[Received: 19 February 2026](Received: 19 February 2026)  \n[Accepted: 6 May 2026](Accepted: 6 May 2026)  \n[Published: 13 May 2026](Published: 13","cbCairUWcQPmeg7V","https://ap.wps.com/l/cbCairUWcQPmeg7V","pdf",9622642,17,"English","# Introduction\n## Purpose\n## Material and Methods\n## Results\n## Conclusion\n## Keywords","[{\"question\":\"What was the study’s main goal?\",\"answer\":\"To determine whether environmentally aged ZnO nanoparticles produce different long-term effects than fresh ZnO nanoparticles on an enhanced aggressive phenotype in HepG2 hepatocellular carcinoma cells.\"},{\"question\":\"How were HepG2 cells exposed and what was measured?\",\"answer\":\"Cells were chronically exposed for about 16 weeks to low-dose aged or fresh ZnO NPs (1.5 µg/mL). RNA sequencing identified transcriptomic changes, and migration/invasion assays evaluated functional outcomes.\"},{\"question\":\"Which molecular pathways and regulators were implicated by the results?\",\"answer\":\"Aged ZnO NPs activated pro-oncogenic pathways such as JAK-STAT and increased cell migration and invasion. Network analysis suggested CEBPA, CTNNB1, and STAT3 as potential core transcriptional regulators.\"},{\"question\":\"What does the conclusion suggest about risk assessment?\",\"answer\":\"Even with lower acute toxicity, chronic exposure to environmentally aged ZnO NPs may promote a more aggressive liver-cell phenotype, suggesting that environmental aging should be considered in nanomaterial risk assessment.\"}]","RNA Sequencing Explores Potential Mechanisms Underlying the Enhanced Aggressive Phenotype of HepG2 Cells Induced by Aged Zinc Oxide Nanoparticles | PDF",1790095339,43]