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Updated: May 28, 2026
An Integrated Raman Spectroscopy and Mass Spectrometry Platform to Study Single-Cell Drug Uptake, Metabolism, and Effects
Published on: January 9, 2020
Deciphering Lipid Metabolic Landscape of Sorafenib-Treated Hepatocellular Carcinoma by Mass Spectrometry Imaging and
Dongsheng Li1, Yuanyuan Tuo2, Luheng Sai2
1First Clinical Medical School, Shanxi Medical University, Taiyuan 030001, China.
Abstract:
Although sorafenib (SOR) is effective for advanced hepatocellular carcinoma (HCC), significant metabolic heterogeneity limits its therapeutic effect. In this study, we employed high-resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) to profile the spatial lipidomic alterations in 3D HepG2 spheroids following SOR treatment. Interestingly, sphingophospholipid and glycerophospholipid metabolism played crucial roles. In an orthotopic HCC mouse model, immunohistochemical and immunofluorescence staining confirmed that SOR induced immunological and inflammatory changes. Moreover, transcriptomic and Q-PCR analyses showed increased expression of Stat1, Zbp1, Parp14, Irf1, and Tifa along with decreased Eif4e2 in the SOR treatment group compared to the tumor control group. Bio-layer interferometry and molecular docking data also indicated that ZBP1 possessed favorable binding affinities with SOR. Overall, our findings demonstrated that SOR dramatically disrupted sphingolipid metabolism in tumor cell spheroids and, in an orthotopic model, activated the NOD-like receptor signaling pathway, accompanied by altered secretion of inflammatory factors and macrophage polarization. These results suggest that SOR exerts dual effects on tumor cell lipid metabolism and the tumor immune microenvironment. These findings provide a conceptual basis for future exploration of lipid-modulating therapeutic strategies in HCC.
Insights
Sorafenib disrupts sphingolipid metabolism in hepatocellular carcinoma (HCC) cells and activates immune pathways in mouse models. This suggests dual effects on tumor lipid metabolism and the immune microenvironment for HCC therapy.
Area of Science:
- Oncology
- Metabolomics
- Immunology
Background:
- Advanced hepatocellular carcinoma (HCC) exhibits metabolic heterogeneity, limiting sorafenib (SOR) efficacy.
- Understanding SOR's impact on lipid metabolism and the immune microenvironment is crucial for improving HCC treatment.
Purpose of the Study:
- To investigate the spatial lipidomic alterations in HCC spheroids treated with SOR.
- To explore the immunological and inflammatory changes induced by SOR in an orthotopic HCC mouse model.
Main Methods:
- High-resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) for spatial lipidomics.
- Immunohistochemistry, immunofluorescence, transcriptomics, and Q-PCR for molecular and immunological analyses.
- Bio-layer interferometry and molecular docking to assess drug-target interactions.
Main Results:
- SOR treatment significantly altered sphingophospholipid and glycerophospholipid metabolism in HCC spheroids.
- SOR induced immunological changes, including increased expression of inflammatory genes (Stat1, Zbp1, Parp14, Irf1, Tifa) and altered macrophage polarization.
- ZBP1 showed favorable binding affinity with SOR, suggesting a potential molecular interaction.
Conclusions:
- SOR disrupts sphingolipid metabolism in HCC tumor cells and activates the NOD-like receptor signaling pathway in vivo.
- SOR exhibits dual effects on tumor cell lipid metabolism and the tumor immune microenvironment.
- Findings support exploring lipid-modulating strategies combined with immunotherapy for HCC treatment.
