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. 2025 Jul:168:156237.
doi: 10.1016/j.metabol.2025.156237. Epub 2025 Mar 22.

Spatial lipidomics reveals sphingolipid metabolism as anti-fibrotic target in the liver

Aleksandra Gruevska  1 , Jack Leslie  2 , Elena Perpiñán  3 , Hannah Maude  1 , Amy L Collins  2 , Sophia Johnson  2 , Laila Evangelista  1 , Eleanor Sabey  1 , Jeremy French  4 , Steven White  4 , John Moir  4 , Stuart M Robinson  4 , Wasfi Alrawashdeh  4 , Rohan Thakkar  4 , Roberta Forlano  1 , Pinelopi Manousou  1 , Robert Goldin  1 , David Carling  5 , Matthew Hoare  6 , Mark Thursz  1 , Derek A Mann  2 , Inês Cebola  1 , Joram M Posma  1 , Niloufar Safinia  3 , Fiona Oakley  7 , Zoe Hall  8
Affiliations
Free article

Spatial lipidomics reveals sphingolipid metabolism as anti-fibrotic target in the liver

Aleksandra Gruevska et al. Metabolism. 2025 Jul.
Free article

Abstract

Background and aims: Steatotic liver disease (SLD), which encompasses various causes of fat accumulation in the liver, is a major cause of liver fibrosis. Understanding the specific mechanisms of lipotoxicity, dysregulated lipid metabolism, and the role of different hepatic cell types involved in fibrogenesis is crucial for therapy development.

Methods: We analysed liver tissue from SLD patients and 3 mouse models. We combined bulk/spatial lipidomics, transcriptomics, imaging mass cytometry (IMC) and analysis of published spatial and single-cell RNA sequencing (scRNA-seq) data to explore the metabolic microenvironment in fibrosis. Pharmacological inhibition of sphingolipid metabolism with myriocin, fumonisin B1, miglustat and D-PDMP was carried out in hepatic stellate cells (HSCs) and human precision cut liver slices (hPCLSs).

Results: Bulk lipidomics revealed increased glycosphingolipids, ether lipids and saturated phosphatidylcholines in fibrotic samples. Spatial lipidomics detected >40 lipid species enriched within fibrotic regions, notably sphingomyelin (SM) 34:1. Using bulk transcriptomics (mouse) and analysis of published spatial transcriptomics data (human) we found that sphingolipid metabolism was also dysregulated in fibrosis at transcriptome level, with increased gene expression for ceramide and glycosphingolipid synthesis. Analysis of human scRNA-seq data showed that sphingolipid-related genes were widely expressed in non-parenchymal cells. By integrating spatial lipidomics with IMC of hepatic cell markers, we found excellent spatial correlation between sphingolipids, such as SM(34:1), and myofibroblasts. Inhibiting sphingolipid metabolism resulted in anti-fibrotic effects in HSCs and hPCLSs.

Conclusions: Our spatial multi-omics approach suggests cell type-specific mechanisms of fibrogenesis involving sphingolipid metabolism. Importantly, sphingolipid metabolic pathways are modifiable targets, which may have potential as an anti-fibrotic therapeutic strategy.

Keywords: Imaging mass cytometry; Lipid metabolism; Liver fibrosis; Mass spectrometry imaging; Steatotic liver disease.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Fiona Oakley and Derek A. Mann reports a relationship with Fibrofind limited that includes: board membership, consulting or advisory, employment, and equity or stocks. Matthew Hoare reports a relationship with Quotient Therapeutics that includes: consulting or advisory. Matthew Hoare reports a relationship with AstraZeneca that includes: consulting or advisory. Matthew Hoare reports a relationship with Boston Scientific that includes: consulting or advisory. Matthew Hoare reports a relationship with Pfizer that includes: funding grants. Inês Cebola's partner reports a relationship with Ochre Bio that includes: equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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