Zhang MY, Sun RQ, Min Q, Zhu YQ, Qin SK, Guo QL. Synergistic antitumor effect of oroxylin A and donafenib in hepatocellular carcinoma through tumor protein p53 signaling pathway activation. World J Gastroenterol 2026; 32(6): 113529 [DOI: 10.3748/wjg.v32.i6.113529]
Corresponding Author of This Article
Mei-Yuan Zhang, Intensive Care Unit, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine/Shanghai Key Laboratory of Embryo Original Disease, Shanghai Municipal Key Clinical Specialty, No. 1567 Jinqian Road, Fengxian District, Shanghai 201499, China. zhangmeiyuan1972@163.com
Research Domain of This Article
Oncology
Article-Type of This Article
Basic Study
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Feb 14, 2026 (publication date) through Feb 5, 2026
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Journal Information of This Article
Publication Name
World Journal of Gastroenterology
ISSN
1007-9327
Publisher of This Article
Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
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Zhang MY, Sun RQ, Min Q, Zhu YQ, Qin SK, Guo QL. Synergistic antitumor effect of oroxylin A and donafenib in hepatocellular carcinoma through tumor protein p53 signaling pathway activation. World J Gastroenterol 2026; 32(6): 113529 [DOI: 10.3748/wjg.v32.i6.113529]
Mei-Yuan Zhang, Intensive Care Unit, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine/Shanghai Key Laboratory of Embryo Original Disease, Shanghai Municipal Key Clinical Specialty, Shanghai 201499, China
Rui-Qian Sun, Qi Min, Yu-Qi Zhu, Shu-Kui Qin, Department of Integrated Traditional Chinese and Western Medicine Clinical Medicine, Nanjing University of Traditional Chinese Medicine, Nanjing 210023, Jiangsu Province, China
Qing-Long Guo, Department of Clinical Pharmacy, Jiangsu Key Laboratory of Carcinogenesis and Intervention, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210018, Jiangsu Province, China
Co-corresponding authors: Mei-Yuan Zhang and Qing-Long Guo.
Author contributions: Zhang MY is responsible for initiating the research, searched data, organized results, and led manuscript drafting; Qin SK and Guo QL formulated the research scheme and provided key guidance on ideas, shaping the study’s framework; Min Q screened valid data from extensive information to ensure analysis reliability; Sun RQ sorted collected data for completeness and standardization; Zhu YQ conducted in-depth statistical analysis to extract conclusions. Zhang MY and Guo QL are co-corresponding authors and contributed equally to this work, including design of the study, acquiring and analyzing data from experiments, and writing of the manuscript. All authors read and approved the final manuscript.
Institutional animal care and use committee statement: The study was approved by the Animal Ethics Committee of International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine (Approval No. 22-12-22).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: All data generated or analyzed during this study are included in this published article.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Mei-Yuan Zhang, Intensive Care Unit, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine/Shanghai Key Laboratory of Embryo Original Disease, Shanghai Municipal Key Clinical Specialty, No. 1567 Jinqian Road, Fengxian District, Shanghai 201499, China. zhangmeiyuan1972@163.com
Received: September 16, 2025 Revised: October 31, 2025 Accepted: December 11, 2025 Published online: February 14, 2026 Processing time: 138 Days and 22.9 Hours
Abstract
BACKGROUND
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.
AIM
To investigate the effects and underlying mechanisms of oroxylin A in combination with donafenib on HCC through in vivo and in vitro studies.
METHODS
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.
RESULTS
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.
CONCLUSION
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.
Core Tip: This study demonstrates that the combination of oroxylin A and donafenib exerts a potent synergistic antitumor effect against hepatocellular carcinoma in vitro and in vivo. Mechanistically, this synergy is achieved through the convergent activation of the tumor-suppressive tumor protein p53 signaling pathway. This work provides a novel and effective therapeutic strategy for hepatocellular carcinoma.
