Liver cancer derived high core fucosylation sEV elict malignancy by activating PI3K/AKT signaling pathway.

Small extracellular vesicles (sEV) play a key role in liver cancer (LC) by supporting cancer cell survival, local invasion, and distant metastasis. Although sEV surfaces are known to be richly glycosylated, how these glycans influence sEV function remains poorly understood. In this study, we observed elevated levels of core fucosylation in LC tissues, serum, and cells, as well as in serum-derived sEV. sEV isolated from highly metastatic MHCC97H cells or from LC patient serum enhanced the proliferation and migration of recipient cells. Conversely, inhibiting core fucosylation on sEV suppressed these malignant phenotypes. Mechanistically, integrated proteomic and glycoproteomic profiling identified lectin galactoside-binding soluble 3-binding protein (LGALS3BP) as significantly enriched in LC serum-derived sEV and modified by core fucosylation. Knockdown of LGALS3BP in donor cells attenuated the malignant behavior of recipient cells by inhibiting PI3K-AKT signaling. Our findings reveal a crucial role for core fucosylation in mediating the pro-tumor functions of LC-derived sEV and suggest that targeting sEV glycosylation may offer a novel therapeutic strategy for LC.