Hederagenin Promotes Sorafenib Sensitivity in Hepatocellular Carcinoma Through Suppressing SLC7A11 Expression and Inducing Ferroptosis

Sorafenib (SOR) significantly improves the survival rate for patients with advanced hepatocellular carcinoma (HCC). Nevertheless, the clinical efficacy is restricted by the development of acquired resistance. Therefore, enhancing susceptibility of HCC cells to SOR is of critical importance for patients with advanced disease. Traditional Chinese medicine (TCM) possesses considerable potential to overcome SOR resistance. Hederagenin (HED), a bioactive triterpenoid molecule with potent antitumor activity, has been reported to markedly reduce chemoresistance to various anticancer drugs in cancer cells. In the present study, we observed that HED synergistically potentiated the anticancer activity of SOR in HCC cells, reducing its IC50 by more than 50%. Further investigations revealed that HED increased SOR‐induced ferroptosis, and inhibition of ferroptosis clearly abrogated this synergistic effect. Mechanistically, SLC7A11, a key regulator of ferroptosis, was identified as a potential target of HED in HCC. And our data further revealed the pronounced upregulation of SLC7A11 in human HCC tissues, whereas HED treatment significantly downregulated its expression, suggesting that SLC7A11 might be a principal molecular target of HED in SOR‐mediated ferroptosis. Furthermore, loss‐ and gain‐of‐function experiments confirmed that SLC7A11 plays an essential role in mediating HED‐enhanced SOR‐induced ferroptosis. In summary, our results demonstrated that HED synergistically promoted the anti‐cancer effects of SOR on HCC cells by suppressing SLC7A11 expression, thereby triggering ferroptosis. These results suggest that HED represents a promising strategy to overcome SOR resistance and offers a viable therapeutic approach to improve SOR efficacy in patients with resistant HCC.