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 clinically investigated.

Conclusion: Development of novel drugs specifically targeting ceramide metabolism could provide an enhanced therapeutic response and improved survival outcome in HCC patients.

背景：肝细胞癌（HCC）由于其不受控制的细胞生长和增殖，侵袭性以及遗传的化学抗性，是全球最大的健康负担之一。尽管目前有针对HCC的不同治疗选择，但具有区域性和远期疾病的HCC患者的5年相对存活率仍然较低，这突出表明迫切需要针对HCC的新型治疗策略。最近的发现强烈表明特定的脂质种类（例如鞘脂）在肿瘤发生中起重要作用。

目的：我们将概述神经酰胺代谢在肝癌的发病机理和治疗中的作用的最新文献发现。

结果：HCC的特征在于神经酰胺代谢失调，这可能归因于神经酰胺合酶2、4和6，酸性和碱性神经酰胺酶2和3的活性和表达改变，以及鞘氨醇激酶（SphK）1的失调。 2和1鞘氨醇磷酸酯，特别是S1PR1。其中，SphK2已成为HCC的临床相关药物靶标，目前正在针对晚期HCC患者的临床试验中研究其对ABC294640的抑制作用。另一个有希望的策略包括恢复肝癌组织中神经酰胺的水平，其中纳米脂质体神经酰胺，特别是C6-神经酰胺已成为抗肝癌的有效治疗剂，其安全性和推荐剂量目前正在临床研究中。

结论：开发专门针对神经酰胺代谢的新药可以提高HCC患者的治疗反应并改善生存率。