Ginsenoside 20(S)-Rg3 upregulates SQLE to reprogram cholesterol metabolism of ovarian cancer cells.

Ginsenoside 20(S)-Rg3 exhibits the anti-ovarian cancer activity by modulating aerobic glycolysis, but its role in reprogramming sterol metabolism remains unclear. This research utilized transcriptomic and lipidomic to identify the key metabolic pathways and targets influenced by 20(S)-Rg3. 20(S)-Rg3 altered 175 mRNAs and 64 metabolites in ovarian cancer cells, and cluster analysis found that the differentially expressed genes and metabolites were highly associated with the steroid biosynthesis. Multi-omics analysis revealed squalene epoxidase (SQLE), a rate-limiting enzyme in steroid biosynthesis, was upregulated by 20(S)-Rg3. Silencing of SQLE attenuated the inhibitory effects of 20(S)-Rg3 on ovarian cancer cell proliferation in vitro and in vivo, as well as cell migration, invasion, and cholesterol synthesis. 20(S)-Rg3 enhanced SQLE expression by downregulating HIF-1α. Co-immunoprecipitation confirmed the interaction between SQLE and farnesyl-diphosphate farnesyltransferase 1 (FDFT1), another rate-limiting enzyme in cholesterol metabolism. These findings suggest that 20(S)-Rg3 exerts anti-ovarian cancer effects by HIF-1α/SQLE/FDFT1 to reprogram cholesterol metabolism.