Abstract

Background Hepatocellular carcinoma (HCC) persists as a therapeutic challenge owing to restricted treatment alternatives and the dearth of effective biomarkers. The creatine transporter SLC6A8 has been documented to participate in the progression of various malignancies. However, the role that SLC6A8 plays in HCC remains poorly characterized. Hence, this study aimed to investigate the function of the SLC6A8 in HCC and evaluate its candidacy as a therapeutic target. Methods Bioinformatics analysis, qPCR on tissue specimens, and immunohistochemistry on tissue microarrays were utilized to assess the expression and clinical significance of SLC6A8 in HCC. In vitro assays including cell viability, colony formation, and cell migration, as well as an in vivo subcutaneous xenograft model, were employed to explore the impacts of both genetic silencing of SLC6A8 and pharmacological blockade of SLC6A8 on HCC tumor growth. The anti-tumor effect of SLC6A8 inhibition in combination with the ferroptosis inducer RSL3 in HCC was also examined in cellular and animal models. Results Our findings revealed that SLC6A8 is notably upregulated in HCC tissues and is associated with a poor prognosis. SLC6A8 knockdown suppressed cell proliferation and migration of HCC cells. RGX-202 also demonstrated potent antitumor efficacy in HCC cells both in vitro and in vivo. Moreover, SLC6A8 inhibition augmented cellular susceptibility to ferroptosis and significantly enhanced the anti-tumor efficacy of the ferroptosis inducer RSL3 in xenograft models of HCC. Conclusion These findings underscore SLC6A8 as a promising therapeutic target, and its inhibitor combined with ferroptosis inducers may serve as an innovative treatment strategy for improving the therapeutic effect in HCC. Supplementary Information The online version contains supplementary material available at 10.1007/s00432-026-06442-8.