Background: Hepatocellular Carcinoma (HCC) is one of the greatest global health burdens
because of its uncontrolled cell growth and proliferation, aggressive nature as well as inherited
chemoresistance. In spite of different treatment options currently available for HCC, the 5-year relative
survival rates for HCC patients with regional and distant stages of the disease are still low,
which highlights the urgent need for novel therapeutic strategies for HCC. Recent findings strongly
suggest that specific lipid species, such as sphingolipids, play a prominent role in tumorigenesis.
Objective: We will give an overview of recent literature findings on the role of ceramide metabolism
in the pathogenesis and treatment of HCC.
Results: HCC is characterised by dysregulation of ceramide metabolism, which could be ascribed to
altered activity and expression of ceramide synthases 2, 4 and 6, and acid and alkaline ceramidases 2
and 3, as well as to deregulation of Sphingosine kinases (SphK) 1 and 2 and sphingosine-1-
phosphate receptors, in particular, S1PR1. Among them, SphK2 has emerged as a clinically relevant
drug target in HCC whose inhibition by ABC294640 is currently being investigated in a clinical trial
in patients with advanced HCC. Another promising strategy includes restoration of ceramide levels
in HCC tissues, whereby nanoliposomal ceramides, in particular C6-ceramide, has emerged as an
effective therapeutic agent against HCC whose safety and recommended dosing is currently being
Conclusion: Development of novel drugs specifically targeting ceramide metabolism could provide
an enhanced therapeutic response and improved survival outcome in HCC patients.