Importantly, we identified the underlying molecular mechanism by which SAF not only downregulates the expression of MARCH1 but also further inhibits the downstream signaling cascades PI3K/AKT/β-catenin and antiapoptotic Mcl-1/Bcl-2 and activates the cleaved caspase-3 and cleaved caspase-7 signaling pathways to repress the development and progression of HCC with respect to growth, apoptosis, cell cycle, migration, and invasion, both in vitro and in vivo. Here, MARCHF1 is linked to hepatocellular carcinoma.