Ginsenoside Rk1 inhibits EMT and the metastasis of hepatocellular carcinoma by affecting the m6A modification of mRNA.

BACKGROUND

N6-methyladenosine (m6A) is a crucial messenger RNA (mRNA) modification that plays a significant role in tumor development and metastasis. Ginsenoside Rk1 possesses notable anticancer activity; however, its effects on m6A modification have not yet been elucidated.

HYPOTHESIS/PURPOSE: In this study, the aim is to investigate the role of ginsenoside Rk1 in the regulation of m6A modification and its effect on hepatocellular carcinoma (HCC) metastasis.

METHODS

The construction of in vitro and in vivo lung metastasis models was used to investigate the effect of ginsenoside Rk1 on lung metastasis of HCC. RNA sequencing, m6A sequencing, siRNA cell transfection, western blotting and quantitative real-time PCR (qRT-PCR) were performed to investigate the effect of ginsenoside Rk1 on m6A modification and its mechanism of action in inhibiting lung metastasis through modulation of m6A modification.

RESULTS

Ginsenoside Rk1 demonstrated dose-dependent inhibition of HCC metastasis both in vivo and in vitro. Mechanistically, it suppressed the expression of Fat mass and obesity-associated protein (FTO), an m6A demethylase, thereby enhancing m6A modification in HCC cells. Specifically, ginsenoside Rk1 significantly increased the m6A modification of Block of proliferation 1 (BOP1) mRNA, leading to prolonged mRNA half-life. Furthermore, ginsenoside Rk1-mediated knockdown of BOP1 expression inhibited Epithelial-mesenchymal transition (EMT) pathway-related proteins (e.g., Vimentin, matrix metalloproteinase-2 (MMP2), and matrix metalloproteinase-9 (MMP9)), thus attenuating the metastatic potential of HCC cells. These findings highlighted the therapeutic potential of ginsenoside Rk1 in mitigating HCC aggressiveness through its dual role in modulating the FTO-m6A-BOP1 axis and inhibiting the EMT pathway.

CONCLUSION

Ginsenoside Rk1 inhibits the migration and invasion of HCC by enhancing FTO-mediated m6A modification of BOP1 mRNA. Ginsenoside Rk1 has the potential to act as an m6A methylation regulator inhibitor, offering a novel approach for targeting m6A modification in the treatment of HCC metastasis.