ORIGINAL RESEARCH article
Front. Oncol.
Sec. Cancer Molecular Targets and Therapeutics
Selinexor Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Sorafenib by Regulating the BAX/Bcl-2/PUMA Apoptotic Pathway and the XPO1/p27 Cell Cycle Pathway
Shenghong Du 1
Ling Wang 1
Chen Chen 1
Yu Sun 2
Qian Liu 3
Jingfei Shi 4
Feng Zhang 5
Kai Wang 5
Cui Chao 2
1. The Affiliated Taian City Central Hospital of Qingdao University, Taian, China
2. Qilu Hospital of Shandong University Dezhou Hospital, Nanjing, China
3. Taian Eightty-Eight Hospital, Taian, China
4. Shandong First Medical University, Jinan, China
5. Qilu Hospital of Shandong University, Jinan, China
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Abstract
This study aimed to investigate the molecular mechanism by which selinexor modulates the sensitivity of hepatocellular carcinoma (HCC) cells to sorafenib. In vivo animal experiments and in vitro cell experiments were performed to systematically analyze the effects of the drug combination on HCC cell proliferation, cycle, apoptosis, and the expression of related signaling pathway proteins. The results showed that combined treatment with selinexor and sorafenib significantly inhibited tumor growth in Huh7 xenograft nude mice, with a superior effect compared to monotherapy groups. In vitro, the two drugs exerted an additive effect in suppressing the proliferation of Huh7, SK-HEP-1, and HepG2 HCC cells, as confirmed by comparing the experimental combination effect with the theoretical additive effect calculated from single-agent data. This additivity also induced marked G1 phase arrest in Huh7 cells and significantly increased the apoptosis rate of Huh7 and HepG2 cells. Mechanistic studies demonstrated that the combination treatment upregulated the expression of pro-apoptotic proteins BAX and PUMA, as well as the cell cycle regulatory protein p27, while downregulating the expression of anti-apoptotic protein Bcl-2 and nuclear export protein XPO1. This study confirms that selinexor enhances the sensitivity of HCC cells to sorafenib by regulating the BAX/Bcl-2/PUMA apoptotic pathway and the XPO1/p27 cell cycle pathway, thereby proposing a novel combination therapy strategy for clinical targeted therapy of HCC. This strategy not only improves the efficacy of sorafenib in primary HCC but also provides an experimental basis for overcoming both intrinsic and acquired sorafenib resistance. This study is limited by the lack of RT-PCR analysis and downstream effector molecule detection, which warrants further investigation in future studies.
Summary
Keywords
Apoptosis pathway, cell cycle pathway, drug sensitivity, Hepatocellular Carcinoma, Selinexor, Sorafenib
Received
09 December 2025
Accepted
20 February 2026
Copyright
© 2026 Du, Wang, Chen, Sun, Liu, Shi, Zhang, Wang and Chao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Cui Chao
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