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Recently, CDK4\u2010targeted inhibitors have shown promise in the treatment of HCC. Our study aimed to evaluate the therapeutic potential of pedunculoside (PE), elucidate its mechanism of action in HCC, and explore its potential as a novel natural CDK4 inhibitor in HCC management. We conducted a series of assays, including the cell counting kit\u20108 (CCK\u20108), colony formation, EdU incorporation, the terminal deoxynucleotidyl transferase (TdT)\u2010mediated dUTP nick end labeling (TUNEL), and flow cytometry to elucidate the effects of PE on cell viability, proliferation, apoptosis, and the cell cycle. Furthermore, in\u00a0vivo experiments using xenograft and lung metastasis models, along with acute toxicity assays, were performed to assess the therapeutic efficacy and toxicity of PE. The underlying mechanisms of PE in HCC were explored through a multifaceted approach, encompassing network pharmacology, molecular docking, the cellular thermal shift assay (CETSA), differential scanning fluorimetry (DARTS), and RNA sequencing. The cell viability, proliferation, and apoptosis results indicated that PE effectively suppressed cell proliferation and enhanced apoptosis through mitochondrial pathways in HCC cells. Moreover, PE exhibited a significant in\u00a0vivo tumor\u2010suppressive effect, reducing tumor volume, size, and lung metastasis. A network pharmacology analysis suggested that PE targets four key proteins, cyclin B1 (CCNB1), cyclin B2 (CCNB2), cyclin\u2010dependent kinase 1 (CDK1), and cyclin\u2010dependent kinase 4 (CDK4), to disrupt the cell cycle. Notably, CDK4 was significantly downregulated by PE treatment both in\u00a0vitro and in\u00a0vivo. Cell overexpression and knockdown experiments demonstrated that PE promoted apoptosis and induced cell cycle arrest in the G1\/S phase by inhibiting CDK4. Molecular docking, CETSA, and DARTS assays confirmed that CDK4 is a direct target for binding and inhibiting PE. RNA sequencing and a series of in\u00a0vitro assays, including p38 pathway inhibition, revealed that PE activates the mitogen\u2010activated protein kinase (MAPK) pathway, exerting a pro\u2010apoptotic effect by inhibiting and binding to CDK4. Our findings demonstrate that PE directly binds to and inhibits CDK4, thereby inducing cell cycle arrest at the G1\/S phase, activating the p38 MAPK pathway, and ultimately promoting cell apoptosis and suppressing HCC progression. These findings highlight the potential of PE as a unique therapeutic agent for HCC treatment.<\/jats:p>","DOI":"10.1002\/ptr.70308","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T07:13:29Z","timestamp":1773990809000},"page":"3171-3189","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pedunculoside Inhibits Hepatocellular Carcinoma Progression by Activating the\n                    <scp>MAPK<\/scp>\n                    Signaling Pathway Through Targeting and Suppressing\n                    <scp>CDK4<\/scp>"],"prefix":"10.1002","volume":"40","author":[{"given":"Yang","family":"Zhou","sequence":"first","affiliation":[{"name":"Jiangsu Province Engineering Research Center of Molecular Target Therapy and Companion Diagnostics in Oncology, Pharmacy Department Suzhou Vocational Health College  Suzhou 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