Notably, in vitro experiments and xenograft models have demonstrated the potential of SphK2 to inhibit HCC, recent evidence reveals that it mediates resistance to regorafenib (a standard second-line treatment drug for advanced HCC) by activating the NF-κB/STAT3 signaling pathway, suggesting that the SphK2/S1P axis may exert oncogenic effects in the HCC microenvironment (39). Here, STAT3 is linked to hepatocellular carcinoma.