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Background:  The specific impact of sphingolipid metabolism on developing hepatocellular Carcinoma (HCC) remains unclear. This study aims to explore the relationship between sphingolipid metabolism and HCC prognosis, immune response, and drug sensitivity.  Methods:  Data were obtained from The Cancer Genome Atlas (TCGA)-Hepatocellular Carcinoma (LIHC) and Gene Expression Omnibus (GEO, GSE14520 datasets). 47 sphingolipid metabolism genes were obtained from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. After classifying HCC samples using the Non-negative Matrix Factorization (NMF) clustering method, differentially expressed genes were screened. Then, 8 risk genes were obtained by univariate analysis, survival random forest reduction and lasso analysis. The expression of 8 risk genes was verified  in vitro .  Results:  8 risk genes were used to construct the Sphingolipid score model. High-Sphingolipid score predicted poor prognosis of HCC patients. Sphingolipid score was associated with immune checkpoints ( IL-1B ,  TLR4 ,  TGFB1 , and  IL-10 ), immune cells (Th2, Treg, MDSC, Neutrophil, Fibroblasts and macrophage), and MAPK Cascade. In the High-Sphingolipid score group, a significantly higher proportion of patients with  TP53  ( p53 ) mutations was significantly higher (56%). Furthermore, patients with a high-Sphingolipid score were predicted to have a higher sensitivity to chemotherapy drugs.  In vitro  validation showed that compared with normal liver cells LX-2,  TRIM47 , and  S100A9  significantly increased in liver cancer cells Hep G2, MHCC-97H, and Hep3B2.1-7, while  SLC1A7 ,  LPCAT1 , and  CFHR4  significantly decreased. Silencing  TRIM47  reduced the proliferation and promoted apoptosis. The levels of ceramide synthesis-related indexes (CERS1, CERS6, CERS5, and SPTLC2) increased, and the ACER3 related to catalytic hydrolysis decreased.  Conclusion:  We constructed a sphingolipid metabolism-related prognostic signature (Sphingolipid score) based on 8 risk genes.  TRIM47  may affect the development of liver cancer by regulating the relevant indicators of ceramide synthesis and catalytic hydrolysis.

Identification prognostic features related to sphingolipid metabolism and experimental validation of TRIM47 in hepatocellular carcinoma