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Transcriptomics, lipidomics, and single-nucleus RNA sequencing integration: exploring sphingolipids in MASH-HCC
Jing Zeng1,2, Grayson Way1, Nan Wu1
1Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond Veterans Affairs Medical Center, 1220 East Broad Street, Richmond, VA, MMRB-5044, 23298-0678, USA.
Cell & Bioscience
|March 8, 2025
Summary
Sphingolipid metabolism changes are key in metabolic dysfunction-associated steatohepatitis (MASH) progression to liver cancer (HCC). Specific sphingolipid profiles in serum and liver show promise as biomarkers for MASH-HCC diagnosis and prognosis.
Area of Science:
- Hepatology
- Molecular Biology
- Cancer Research
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) spectrum includes simple steatosis, MASH, and cirrhosis.
- MASLD is a growing cause of liver transplantation and a risk factor for hepatocellular carcinoma (HCC).
- Sphingolipid metabolism dysregulation is implicated in MASH-HCC development, but detailed profiles and cell-specific gene changes are poorly understood.
Purpose of the Study:
- To investigate sphingolipid profiles and cell type-specific gene expression in MASH-HCC progression.
- To identify key genes and molecular pathways involved in sphingolipid metabolism during MASH-HCC development.
- To evaluate the prognostic significance of sphingolipid-related genes in human MASH-HCC.
Main Methods:
- Utilized a diet-induced MASH-HCC mouse model (DIAMOND).
- Employed total RNA sequencing, NanoString gene profiling, and single-nucleus RNA sequencing (snRNA-seq).
- Performed targeted lipidomics for serum and liver sphingolipid profiling and analyzed TCGA-LIHC patient data.
Main Results:
- Identified dysregulation of key sphingolipid metabolism genes (e.g., CERS6, SPTLC2, SphK2, S1PR1-3) correlating with altered serum and liver sphingolipid levels.
- Univariate and multivariate Cox analyses revealed prognostic significance of CERS6, SPTLC2, and S1PR1 in MASH-HCC.
- snRNA-seq provided cell type-specific insights into gene regulation during MASH-HCC progression.
Conclusions:
- Sphingolipids play a critical role in the progression from MASH to HCC.
- Distinct serum and liver sphingolipid profiles may serve as diagnostic and prognostic biomarkers for MASH-HCC.
- Understanding sphingolipid metabolism offers potential therapeutic targets for MASH-HCC.
