{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:12:04Z","timestamp":1759191124612,"version":"3.44.0"},"reference-count":49,"publisher":"PeerJ","license":[{"start":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T00:00:00Z","timestamp":1752019200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:sec>\n               <jats:title>Background<\/jats:title>\n               <jats:p>Previous studies on patients and rats with hepatocellular carcinoma (HCC) have shown significant changes in the extracellular matrix (ECM). Versican, a component of the ECM, forms extensive multimolecular interactions with other ECM components, particularly hyaluronan, through specific domains in its core protein. However, disturbances in the hyaluronan-versican interaction may affect cancer development. We aimed to examine the effect of modulating matrix cross-linkage between hyaluronan and versican using genipin on tumor cell survival, resistance, and renewal.<\/jats:p>\n            <\/jats:sec>\n            <jats:sec>\n               <jats:title>Methods<\/jats:title>\n               <jats:p>Following the induction of HCC in rats using thioacetamide, an oral dose of 10 mg\/kg of genipin was administered. Liver impairment was evaluated by measuring serum \u03b1-fetoprotein (AFP) levels and examining liver sections stained with hematoxylin\/eosin and anti-versican and anti-fibronectin antibodies. Additionally, hepatic expression levels of mRNA and proteins, including epidermal growth factor (EGF), epidermal growth factor receptor (EGFR), fibronectin, glycogen synthase kinase-3 beta (GSK-3\u03b2), protein kinase B (PKB), and versican, were analyzed.<\/jats:p>\n            <\/jats:sec>\n            <jats:sec>\n               <jats:title>Results<\/jats:title>\n               <jats:p>Genipin enhances rats\u2019 survival, leading to reduction in serum AFP levels and number of hepatic nodules. Micro-imaging examinations reveal that genipin reduces vacuolated cytoplasm, apoptotic nuclei, and necrotic nodules. Additionally, it significantly lowers EGF, EGFR, fibronectin, GSK-3\u03b2, PKB, and versican expression levels.<\/jats:p>\n            <\/jats:sec>\n            <jats:sec>\n               <jats:title>Conclusion<\/jats:title>\n               <jats:p>Genipin may be considered novel anticancer agent with hepatoprotective effects. This is achieved by reducing versican-free forms. Additionally, genipin decreases tumor cells\u2019 resistance by lowering the expression of EGF, EGFR, PKB, and GSK-3\u03b2. Finally, it reduces tumor cell survival by decreasing the expression of fibronectin.<\/jats:p>\n            <\/jats:sec>","DOI":"10.7717\/peerj.19680","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T14:19:16Z","timestamp":1759155556000},"page":"e19680","source":"Crossref","is-referenced-by-count":0,"title":["Effect of modulating the extracellular matrix cross linkage by genipin on tumor cell resistance and survival in thioacetamide-induced hepatocellular carcinoma in rats"],"prefix":"10.7717","volume":"13","author":[{"given":"Hanan M.","family":"Hassan","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Biochemistry, Delta University for Science and Technology, Gamasa, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammed","family":"Baradwan","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, King Abdul Aziz University, Jeddah, Saudi 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