ArticleCellular oncology (Dordrecht, Netherlands)2026
Single-cell mapping of cholesterol metabolism reveals FDPS as a therapeutic vulnerability in hepatocellular carcinoma.
Article in Cellular oncology (Dordrecht, Netherlands), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
purposeDysregulated 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.
methodsAn 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.
resultsCholesterol 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.
conclusionOur 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.
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