Rhaponticin Reverses the Hypoxia-mediated Sorafenib Resistance of Hepatocellular Carcinoma Cells by Inhibiting Epithelial–Mesenchymal Transition

Background Hepatocellular carcinoma (HCC) is a major global health threat with a high mortality rate. Sorafenib, the standard treatment for advanced HCC, is often rendered ineffective by tumor drug resistance, particularly under hypoxic conditions that promote resistance and epithelial–mesenchymal transition (EMT) in cancer cells. Traditional Chinese medicine (TCM), with its anti-tumor components, offers a potential avenue for overcoming resistance and inhibiting EMT. Purpose Rhaponticin (RA), an active compound from TCM, is investigated in this study for its ability to counter hypoxia-induced sorafenib resistance and EMT in HCC cells. Materials and Methods HepG2 and Huh7 cells were cultivated under hypoxic conditions to evaluate sorafenib resistance, with cell proliferation assessed using 5-ethynyl-2′-deoxyuridine (EdU) staining and EMT markers analyzed post-treatment. Then, RA’s capacity to diminish cell viability, enhance sorafenib sensitivity, and reverse EMT was examined. The EMT inhibitor C19 was employed to verify the EMT-dependent nature of RA’s effects. Results Hypoxia increased sorafenib half maximal inhibitory concentration (IC 50 ) values in HCC cells, indicating sorafenib resistance. Its inhibitory effect on EMT was reduced under hypoxia, as shown by altered EMT marker expression. RA treatment decreased HCC cell viability without toxicity to normal liver cells, enhanced sorafenib’s sensitivity, and reversed EMT under hypoxia, evidenced by increased E-cadherin and decreased Vimentin and N-cadherin. The EMT inhibitor negated the nullified RA effect on sorafenib sensitivity, confirming RA EMT-dependent action. Conclusion RA can re-sensitize HCC cells to sorafenib by inhibiting hypoxia-mediated EMT, presenting a promising therapeutic approach for HCC.