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This study aimed to investigate the antitumor effects of periplogenin, a bioactive compound derived from Cortex Periplocae, and to explore its underlying mechanisms in HCC. A series of in\u00a0vitro assays, including scratch wound healing, transwell migration, EdU proliferation, colony formation, flow cytometry, and senescence\u2010associated \u03b2\u2010galactosidase staining, were employed to evaluate the effects of periplogenin on HCC cell migration, proliferation, cell cycle progression, and cellular senescence. Molecular docking and cellular thermal shift assay (CETSA) were used to examine the binding interaction between periplogenin and FOXO1. Protein expression levels were analyzed by western blotting and immunofluorescence. In\u00a0vivo antitumor efficacy was assessed using a xenograft model in BALB\/c\u2010nude mice. Periplogenin significantly inhibited the migration, proliferation, and colony formation of HCC cells. It induced G2\/M phase cell cycle arrest and promoted cellular senescence. Mechanistic studies revealed that periplogenin directly binds to FOXO1, enhances its protein stability, and activates the FOXO1\/P53 signaling pathway, leading to upregulation of senescence\u2010related markers P21 and P16. In\u00a0vivo results demonstrated that periplogenin effectively suppressed tumor growth in a xenograft mouse model without apparent toxicity. Our findings indicate that periplogenin suppresses hepatocarcinogenesis by inducing cellular senescence through activation of the FOXO1\/P53 pathway. These results highlight the potential of periplogenin as a novel therapeutic agent for the treatment of hepatocellular carcinoma.<\/jats:p>","DOI":"10.1002\/ptr.70256","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T17:02:12Z","timestamp":1771606932000},"page":"2588-2603","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Periplogenin Suppresses Hepatocarcinogenesis by Inducing Cellular Senescence via the Activating\n                    <i>FOXO1\/P53<\/i>\n                    Signaling Pathway"],"prefix":"10.1002","volume":"40","author":[{"given":"Peizhen","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Medical Oncology The First Affiliated Hospital of Wenzhou Medical University  Wenzhou Zhejiang China"},{"name":"Department of Pathology The First Affiliated Hospital of Wenzhou Medical University  Wenzhou Zhejiang 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