{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T13:08:37Z","timestamp":1780664917071,"version":"3.54.1"},"reference-count":86,"publisher":"Baishideng Publishing Group Inc.","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["World J Gastroenterol"],"abstract":"<jats:p>BACKGROUND<\/jats:p>\n                  <jats:p>The clinical application of donafenib in advanced hepatocellular carcinoma (HCC) is restricted by its limited therapeutic efficacy and a variety of treatment-associated adverse events. These factors collectively underscore the need for more effective and well-tolerated therapeutic strategies.<\/jats:p>\n                  <jats:p>AIM<\/jats:p>\n                  <jats:p>To investigate the effects and underlying mechanisms of oroxylin A in combination with donafenib on HCC through in vivo  and in vitro  studies.<\/jats:p>\n                  <jats:p>METHODS<\/jats:p>\n                  <jats:p>The antitumor efficacy of oroxylin A, donafenib, and their combination was assessed in xenograft mouse models and MHCC-97H\/PLC-PRF-5 cell lines. Tumor growth was monitored using fluorescence live imaging. Cell viability, colony formation, and apoptosis were assessed using Cell Counting Kit-8, clonogenic, and flow cytometry assays, respectively. Molecular mechanisms were investigated by assessing the expression of tumor protein p53 (TP53) signaling-related regulators via  quantitative real-time polymerase chain reaction, western blot, and immunohistochemistry. Public datasets and Kaplan-Meier analysis were used to analyzed the relationship between their expression and patient survival.<\/jats:p>\n                  <jats:p>RESULTS<\/jats:p>\n                  <jats:p>The combination of oroxylin A and donafenib demonstrated superior anti-tumor efficacy in vivo  compared to monotherapies, without inducing significant hepatorenal toxicity. The combination therapy demonstrated a stronger anti-proliferative and pro-apoptotic effects than two monotherapies in two HCC cell lines. Mechanistically, the drug combination synergistically activated the TP53 signaling pathway. Oroxylin A primarily targeted the cyclin-dependent kinase 9-murine double minute 2 (MDM2)\/MDM4 axis to stabilize TP53, while donafenib suppressed the vascular endothelial growth factor receptor\/B-rapidly accelerated fibrosarcoma proto-oncogene serine\/threonine kinase axis to activate TP53. Clinical data has verified that the upregulation of key components of this pathway (TP53, MDM2, MDM4, and cyclin-dependent kinase 9) in patients with HCC is associated with a poor overall survival.<\/jats:p>\n                  <jats:p>CONCLUSION<\/jats:p>\n                  <jats:p>Oroxylin A and donafenib exert a synergistic anti-tumor effect in HCC by co-activating the TP53 signaling pathway through distinct but complementary molecular axes. This combination strategy presents a promising and viable therapeutic approach to overcome the limitations of donafenib monotherapy in the treatment of HCC.<\/jats:p>","DOI":"10.3748\/wjg.v32.i6.113529","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T06:53:43Z","timestamp":1770015223000},"source":"Crossref","is-referenced-by-count":1,"title":["Synergistic antitumor effect of oroxylin A and donafenib in hepatocellular carcinoma through tumor protein p53 signaling pathway activation"],"prefix":"10.3748","volume":"32","author":[{"given":"Mei-Yuan","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui-Qian","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Min","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Qi","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Kui","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing-Long","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2060","published-online":{"date-parts":[[2026,2,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2021.11.023"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-020-00240-3"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-023-00825-3"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000000520"},{"key":"B5","unstructured":"Asafo-Agyei KO, Samant H.   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