Because nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) are targets of regorafenib and ABC294640, we hypothesized that SphK2/S1P could regulate regorafenib resistance in HCC cells through NF-κB and STAT3 activation. This evidence concerns the gene MBTPS1 and hepatocellular carcinoma.