Scholarlink

Purpose <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusion <p>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Single-cell mapping of cholesterol metabolism reveals FDPS as a therapeutic vulnerability in hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月18日

查看全文
  • Xupeng Yang,
  • Jiajun Li,
  • Yurong Wang,
  • Qiang Gao,
  • Mao Zhang

摘要

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.