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<p>Endocrine-disrupting chemicals (EDCs) are increasingly recognized as environmental contributors to hepatocellular carcinoma (HCC), yet their molecular mechanisms remain poorly understood. This study integrates toxicogenomic, transcriptomic, genetic, and single-cell RNA sequencing data to elucidate how EDCs reprogram hepatic metabolic and immune networks to promote tumorigenesis. By intersecting 5797 EDC-responsive genes with 946 HCC differentially expressed genes, 513 overlapping candidates were identified, enriched in pathways involving hormone signaling, xenobiotic metabolism, lipid regulation, and inflammation. Genetic evidence supported five genes (<i>ESR1</i>, <i>TP53I3</i>, <i>PLIN2</i>, <i>SLC6A12</i>, and <i>SOCS2</i>) as key determinants of HCC susceptibility. These genes exhibited experimentally supported interactions with multiple EDCs, including bisphenol A, diethylhexyl phthalate, and cadmium chloride, implicating them as convergent molecular targets of environmental exposures. Single-cell transcriptomic analysis revealed cell-type-specific expression, notably <i>SOCS2</i> in endothelial cells and <i>PLIN2</i> in myeloid populations, while <i>ESR1</i> displayed sex-dimorphic expression patterns consistent with disrupted estrogen signaling in female HCC. These findings indicate that chronic EDC exposure perturbs hormonal, metabolic, and immune homeostasis, driving hepatic carcinogenesis through coordinated gene network reprogramming. The integrative multi-omics framework presented here provides novel mechanistic insight into the environmental etiology of liver cancer and identifies candidate biomarkers for exposure-linked prevention strategies.</p>

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Endocrine disruptors reprogram hepatic metabolic and immune gene networks to promote hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月3日

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  • Yanggang Hong,
  • Yi Wang,
  • Qingyu Chen,
  • Yirong Wang

摘要

Endocrine-disrupting chemicals (EDCs) are increasingly recognized as environmental contributors to hepatocellular carcinoma (HCC), yet their molecular mechanisms remain poorly understood. This study integrates toxicogenomic, transcriptomic, genetic, and single-cell RNA sequencing data to elucidate how EDCs reprogram hepatic metabolic and immune networks to promote tumorigenesis. By intersecting 5797 EDC-responsive genes with 946 HCC differentially expressed genes, 513 overlapping candidates were identified, enriched in pathways involving hormone signaling, xenobiotic metabolism, lipid regulation, and inflammation. Genetic evidence supported five genes (ESR1, TP53I3, PLIN2, SLC6A12, and SOCS2) as key determinants of HCC susceptibility. These genes exhibited experimentally supported interactions with multiple EDCs, including bisphenol A, diethylhexyl phthalate, and cadmium chloride, implicating them as convergent molecular targets of environmental exposures. Single-cell transcriptomic analysis revealed cell-type-specific expression, notably SOCS2 in endothelial cells and PLIN2 in myeloid populations, while ESR1 displayed sex-dimorphic expression patterns consistent with disrupted estrogen signaling in female HCC. These findings indicate that chronic EDC exposure perturbs hormonal, metabolic, and immune homeostasis, driving hepatic carcinogenesis through coordinated gene network reprogramming. The integrative multi-omics framework presented here provides novel mechanistic insight into the environmental etiology of liver cancer and identifies candidate biomarkers for exposure-linked prevention strategies.