Sophoricoside from sophora japonica L. is efficacious as monotherapy or in combination with lenvatinib in hepatocellular carcinoma via targeting EGFR.

Sophora japonica L. is a commonly used traditional Chinese medicine. Sophoricoside (Sop), the isoflavone glycoside obtained in Sophora japonica L., is demonstrated with various pharmacological activities, such as anticancer, anti-inflammation, and immunosuppression. To data, there is a lack of comprehensive research examining the biological activity of Sop in hepatocellular carcinoma (HCC). The present work focused on investigating effects of Sop on treating HCC and exploring its underlying mechanisms. Here, we found that the treatment of Sop suppressed HCC cell proliferation and survival, arrested HCC cell cycle in vitro, and attenuated HCC growth in vivo. Additionally, Sop combined with lenvatinib elicited the synergy to resist HCC both in vitro and in vivo. Mechanistically, Sop could directly interact with epidermal growth factor receptor (EGFR) to induce its degradation. Such augmented antitumor impact of lenvatinib by Sop was achieved by suppressing the AKT and STAT3 signaling pathways. In conclusion, Sop serves as the strong EGFR inhibitor and the potential natural anti-tumor drug, which can be the sensitizer of lenvatinib for treating HCC via EGFR-AKT/STAT3 signaling, presenting auspicious implications for novel anti-HCC treatment strategies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-025-33330-x.