Critical Roles of the Sphingolipid Metabolic Pathway in Liver Regeneration, Hepatocellular Carcinoma Progression and Therapy

Simple Summary The sphingolipid metabolic pathway, an important signaling pathway, plays a crucial role in various physiological processes including immune regulation, cell proliferation, survival, and apoptosis. Recent studies have suggested that the metabolites from this pathway, such as ceramide, sphingosine 1-phosphate, and sphingosine 1-phosphate receptor, may have therapeutic potential for liver regeneration, fibrosis, and hepatocellular carcinoma (HCC). This review summarizes the mechanisms and therapeutic strategies targeting the sphingolipid metabolic pathway in liver regeneration, fibrosis, and HCC.Abstract The sphingolipid metabolic pathway, an important signaling pathway, plays a crucial role in various physiological processes including cell proliferation, survival, apoptosis, and immune regulation. The liver has the unique ability to regenerate using bioactive lipid mediators involving multiple sphingolipids, including ceramide and sphingosine 1-phosphate (S1P). Dysregulation of the balance between sphingomyelin, ceramide, and S1P has been implicated in the regulation of liver regeneration and diseases, including liver fibrosis and hepatocellular carcinoma (HCC). Understanding and modulating this balance may have therapeutic implications for tumor proliferation, progression, and metastasis in HCC. For cancer therapy, several inhibitors and activators of sphingolipid signaling, including ABC294640, SKI-II, and FTY720, have been discussed. Here, we elucidate the critical roles of the sphingolipid pathway in the regulation of liver regeneration, fibrosis, and HCC. Regulation of sphingolipids and their corresponding enzymes may considerably influence new insights into therapies for various liver disorders and diseases.