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Chitosan-coated iron oxide nanocomposite (Fe<jats:sub>3<\/jats:sub>O<jats:sub>4<\/jats:sub>\/Cs) is a promising bio-nanomaterial for many biological applications. The objective of this research was to evaluate the anticancer efficacy of Fe<jats:sub>3<\/jats:sub>O<jats:sub>4<\/jats:sub>\/Cs against HCC in animal models. Fe<jats:sub>3<\/jats:sub>O<jats:sub>4<\/jats:sub> nanoparticles were prepared and added to chitosan solution; then, the mixture was exposed to gamma radiation at a dose of 20\u00a0kGy. Rats have received diethylnitrosamine (DEN) orally at a dose of 20\u00a0mg\/kg body weight 5 times per week during a period of 10\u00a0weeks to induce HCC and then have received Fe<jats:sub>3<\/jats:sub>O<jats:sub>4<\/jats:sub>\/Cs intraperitoneal injection at a dose of 50\u00a0mg\/kg body weight 3 times per week during a period of 4\u00a0weeks. After the last dose of Fe<jats:sub>3<\/jats:sub>O<jats:sub>4<\/jats:sub>\/Cs administration, animals were sacrificed. DEN induced upregulation of PI3K\/Akt\/mTOR and MAPK (ERK, JNK, P38) signaling pathways and inflammatory markers (TLR4, iNOS, and TNF-\u03b1). DEN also decreases cleaved caspase-3 and increases liver enzymes (ALT, AST, and GGT) activities. Administration of Fe<jats:sub>3<\/jats:sub>O<jats:sub>4<\/jats:sub>\/Cs significantly ameliorated the above-mentioned parameters.<\/jats:p>","DOI":"10.1007\/s12011-022-03221-7","type":"journal-article","created":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T05:02:31Z","timestamp":1658466151000},"page":"1274-1285","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Antitumor Activity of Chitosan-Coated Iron Oxide Nanocomposite Against Hepatocellular Carcinoma in Animal Models"],"prefix":"10.1007","volume":"201","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9211-0009","authenticated-orcid":false,"given":"Monda M. 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