Single-cell mapping of cholesterol metabolism reveals FDPS as a therapeutic vulnerability in hepatocellular carcinoma.
[PURPOSE] Dysregulated cholesterol metabolism has emerged as a crucial driver of hepatocellular carcinoma (HCC) progression and immunotherapy resistance.
APA
Yang X, Li J, et al. (2026). Single-cell mapping of cholesterol metabolism reveals FDPS as a therapeutic vulnerability in hepatocellular carcinoma.. Cellular oncology (Dordrecht, Netherlands), 49(2), 47. https://doi.org/10.1007/s13402-026-01177-7
MLA
Yang X, et al.. "Single-cell mapping of cholesterol metabolism reveals FDPS as a therapeutic vulnerability in hepatocellular carcinoma.." Cellular oncology (Dordrecht, Netherlands), vol. 49, no. 2, 2026, pp. 47.
PMID
41706364
Abstract
[PURPOSE] Dysregulated cholesterol metabolism has emerged as a crucial driver of hepatocellular carcinoma (HCC) progression and immunotherapy resistance. This study aimed to delineate the single-cell landscape of cholesterol metabolism in HCC and identify key molecular determinants linking metabolic reprogramming to tumor aggressiveness and immune evasion.
[METHODS] An integrative multi-omics approach combining bulk and single-cell RNA sequencing from multiple-center cohorts was employed. Metabolic activity scoring, high-dimensional weighted gene co-expression network analysis (hdWGCNA), and a five-model integrated machine learning strategy were applied to identify hub genes associated with cholesterol metabolism. Functional assays, including genetic silencing, metabolic profiling, and orthotopic mouse models with anti-PD-1 and FDPS inhibitor (alendronic acid), were used to validate mechanistic and therapeutic relevance.
[RESULTS] Cholesterol metabolic activity was markedly elevated in HCC tumors and immune checkpoint blockade (ICB) non-responders, with pronounced intratumoral heterogeneity across malignant cell subpopulations. The enzyme Farnesyl Diphosphate Synthase (FDPS) emerged as a pivotal regulator, promoting tumor cell cholesterol metabolism and proliferation. Further functional experiments demonstrated that targeting FDPS suppressed tumor growth, reduced intracellular cholesterol levels and significantly enhanced anti-PD-1 efficacy in vivo, accompanied by increased lymphoid immune infiltration.
[CONCLUSION] Our findings establish FDPS-driven cholesterol metabolic reprogramming as a key mechanism of HCC malignancy and immunotherapy resistance. Targeting FDPS offers a promising strategy to potentiate immune checkpoint therapy and reshape metabolic vulnerabilities in liver cancer.
[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s13402-026-01177-7.
[METHODS] An integrative multi-omics approach combining bulk and single-cell RNA sequencing from multiple-center cohorts was employed. Metabolic activity scoring, high-dimensional weighted gene co-expression network analysis (hdWGCNA), and a five-model integrated machine learning strategy were applied to identify hub genes associated with cholesterol metabolism. Functional assays, including genetic silencing, metabolic profiling, and orthotopic mouse models with anti-PD-1 and FDPS inhibitor (alendronic acid), were used to validate mechanistic and therapeutic relevance.
[RESULTS] Cholesterol metabolic activity was markedly elevated in HCC tumors and immune checkpoint blockade (ICB) non-responders, with pronounced intratumoral heterogeneity across malignant cell subpopulations. The enzyme Farnesyl Diphosphate Synthase (FDPS) emerged as a pivotal regulator, promoting tumor cell cholesterol metabolism and proliferation. Further functional experiments demonstrated that targeting FDPS suppressed tumor growth, reduced intracellular cholesterol levels and significantly enhanced anti-PD-1 efficacy in vivo, accompanied by increased lymphoid immune infiltration.
[CONCLUSION] Our findings establish FDPS-driven cholesterol metabolic reprogramming as a key mechanism of HCC malignancy and immunotherapy resistance. Targeting FDPS offers a promising strategy to potentiate immune checkpoint therapy and reshape metabolic vulnerabilities in liver cancer.
[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s13402-026-01177-7.
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