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Natural products are considered a renewable source, providing inspiring chemical moieties that could be used for cancer treatment. <jats:italic>Suaeda vermiculata Forssk<\/jats:italic> has traditionally been employed for management of hepatic conditions, including liver inflammation, and liver cirrhosis, as well as to improve general liver function. The findings of our earlier study demonstrated encouraging in vivo hepatoprotective benefits against liver injury generated by paracetamol and carbon tetrachloride. Additionally, <jats:italic>Suaeda vermiculata Forssk<\/jats:italic> exhibited cytotoxic activities in vitro against Hep\u2010G2 cell lines and cell lines resistant to doxorubicin. The present investigation aimed to examine the potential in vivo hepatoprotective efficacy of <jats:italic>Suaeda vermiculata Forssk<\/jats:italic> extract (SVE) against hepatocellular carcinoma induced by diethylnitrosamine (DENA) in rats. The potential involvement of the PI3K\/AKT\/mTOR\/NF\u2010\u03baB pathway was addressed. Sixty adult male albino rats were allocated into five groups randomly (<jats:italic>n<\/jats:italic>\u2009=\u200910). First group received a buffer, whereas second group received SVE only, third group received DENA only, and fourth and fifth groups received high and low doses of SVE, respectively, in the presence of DENA. Liver toxicity and tumor markers (HGFR, p\u2010AKT, PI3K, mTOR, NF\u2010\u03baB, FOXO3a), apoptosis markers, and histopathological changes were analyzed. The current results demonstrated that SVE inhibited PI3K\/AKT\/mTOR\/NF\u2010\u03baB pathway as well as increased expression of apoptotic parameters and FOXO3a levels, which were deteriorated by DENA treatment. Furthermore, SVE improved liver toxicity markers and histopathological changes induced by DENA administration. This study provided evidence for the conventional hepatoprotective properties attributed to SV and investigated the underlying mechanism by which its extract, SVE, could potentially serve as a novel option for hepatocellular carcinoma (HCC) treatment derived from a natural source.<\/jats:p>","DOI":"10.1002\/tox.24217","type":"journal-article","created":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T13:04:46Z","timestamp":1710939886000},"page":"3666-3678","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Targeting the <scp>PI3K<\/scp>\/<scp>pAKT<\/scp>\/<scp>mTOR<\/scp>\/<scp>NF\u2010\u03baB<\/scp>\/<scp>FOXO3a<\/scp> signaling pathway for suppressing the development of hepatocellular carcinoma in rats: Role of the natural remedic <i>Suaeda vermiculata<\/i> forssk"],"prefix":"10.1002","volume":"39","author":[{"given":"Mohamed S.","family":"Abdel\u2010Bakky","sequence":"first","affiliation":[{"name":"Department 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