Microbiota-derived SSL6 enhances the sensitivity of hepatocellular carcinoma to sorafenib by down-regulating glycolysis.

Enhancing the sensitivity of hepatocellular carcinoma (HCC) cells to sorafenib (SFN) is an essential clinical bottleneck to be solved. Here we report that the expression of CD47 negatively correlated with HCC sensitivity to SFN. The microbiota-derived Staphylococcal superantigen-like protein 6 (SSL6) inhibited CD47 and promoted SFN-induced apoptosis of HCC cells Huh-7 and MHCC97H. Mechanistically, the sensitivity of HCC cells to SFN was inhibited by elevated Warburg effect (glycolysis), and SSL6 down-regulated PI3K/Akt-mediated glycolysis by blocking CD47. Knockdown of CD47 also dampened glycolysis and sensitized HCC cells to SFN. Moreover, SFN-resistant HCC cells exhibited enhanced glycolysis and CD47 expression. SSL6 significantly re-sensitized the resistant HCC cells to SFN. More importantly, we identified the anti-tumor effect of SSL6 in combination with SFN in HCC-bearing mice. Our results clarify the mechanism by which SSL6 enhances SFN sensitivity in HCC cells, providing a molecular basis for combination targeted therapy with microbiota-derived SSL6 to treat HCC.