We also highlighted the S1P1-PI3K/AKT-heparanase (HPSE) -MMP-7 and S1P1/HPSE-ERK1/2 signaling axes in HCC, which is responsible for S1P-induced shedding and -inhibited synthesis of syndecan-1, leading to TGF-β1 production. Here, HPSE is linked to hepatocellular carcinoma.