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.

Introduction: Sorafenib remains the first-line targeted therapy for advanced hepatocellular carcinoma (HCC), but its clinical efficacy is severely limited by intrinsic and acquired drug resistance. Dysregulation of the BAX/Bcl-2/PUMA apoptotic pathway and XPO1/p27 cell cycle pathway is closely associated with sorafenib resistance. This study aimed to explore whether selinexor, a selective nuclear export inhibitor, could enhance the sensitivity of HCC cells to sorafenib and to clarify the underlying molecular mechanism. Methods: A series of Results: Selinexor combined with sorafenib significantly inhibited tumor growth in nude mice, with a stronger inhibitory effect than monotherapy. Discussion: 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. The combination strategy provides a novel potential approach for improving the therapeutic efficacy of sorafenib and overcoming both intrinsic and acquired sorafenib resistance in HCC. The main limitations of this study are the lack of RT-PCR verification and further detection of downstream apoptotic effector molecules, which need to be explored in future research.