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. • S. aureus -derived protein SSL6 significantly enhances the sensitivity of HCC cells to sorafenib. • SSL6 enhances sorafenib sensitivity of HCC cells by inhibiting glycolysis via CD47/PI3K/Akt signaling pathway. • SSL6 can also reverse the tolerance of sorafenib-resistant HCC cells. • SSL6 and sorafenib synergistically exhibit anti-tumor effects in vivo.