Ginsenoside Rh₃ enhances regorafenib efficacy in hepatocellular carcinoma by modulating FGFR4-STAT3-YAP signaling...

Efforts to develop more effective and safer cancer therapies have driven growing interest in combination treatments using well-established agents. Here we investigate whether ginsenoside Rh₃, a bioactive constituent of Panax ginseng, enhances the anticancer properties of regorafenib, a multikinase inhibitor, in hepatocellular carcinoma (HCC). Although ginsenosides are primarily recognized for immunomodulatory and antioxidant properties, their wider therapeutic applications, particularly in oncology, are being actively investigated. Among the ginsenosides tested, ginsenosides Rh₃ produced the greatest reduction in HCC cell viability when combined with regorafenib. To elucidate the basis of synergy, we conducted proteomic profiling using phosphor-kinase activity assay; the combination of regorafenib and ginsenoside Rh₃ attenuated phosphorylation of signal transducer and activator of transcription 3 (STAT3) and concomitantly upregulated pro-apoptotic proteins. These effects were associated with inactivation of FGFR4 and JAK2, key regulators of cell growth and apoptosis, and dependent on blocking STAT3 nuclear translocation. Notably, the combination treatment also suppressed TEA domain family transcription factor (TEAD)-dependent transcription without promoting nuclear accumulation of yes-associated protein (YAP). The findings suggest that the observed synergy in HCC is linked to inhibition of the FGFR4/JAK2/STAT3 axis and attenuation of YAP-TEAD transcriptional activity, warranting further clinical evaluation of this combination.