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Background <p>Hepatocellular carcinoma (HCC) has limited therapeutic efficacy at advanced stages. Lipid metabolism reprogramming drives HCC progression; however, the functional crosstalk between CYP19A1, GPER1, and lipid metabolic dysregulation in HCC remains unclear.</p> Methods <p>Integrated analyses of The Cancer Genome Atlas Liver Hepatocellular Carcinoma data were performed. Clinical validation, functional assays, rescue experiments, in vivo xenografts, and molecular docking were conducted.</p> Results <p>CYP19A1 was identified as a prognostic hub in HCC, with overexpression correlating with advanced T/BCLC stages (<i>p</i> &lt; 0.05) and poor survival (log-rank <i>p</i> &lt; 0.05). Gene set enrichment analysis linked CYP19A1 to dysregulated lipid metabolism, pro-tumorigenic signaling, and immune infiltration. GPER1 was found to be a critical effector of CYP19A1, mediating its effects on proliferation, migration, invasion, epithelial–mesenchymal transition, and protein kinase B activation. CYP19A1 knockdown reduced tumor burden in vivo, whereas <i>GPER1</i> overexpression rescued this phenotype.</p> Conclusion <p>The CYP19A1-GPER1 axis represents a critical oncogenic driver in HCC, providing a mechanistic insight to guide future therapeutic development.</p>

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Identification of the CYP19A1-GPER1 axis as a critical oncogenic driver in hepatocellular carcinoma via AKT activation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月19日

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  • Hang Zhai,
  • Jicai Wang,
  • Yongfei He,
  • Shengjie Hong,
  • Kai Huang,
  • Shuai Hu,
  • Shuang Hao,
  • Guangquan Zhang,
  • Xianjie Shi

摘要

Background

Hepatocellular carcinoma (HCC) has limited therapeutic efficacy at advanced stages. Lipid metabolism reprogramming drives HCC progression; however, the functional crosstalk between CYP19A1, GPER1, and lipid metabolic dysregulation in HCC remains unclear.

Methods

Integrated analyses of The Cancer Genome Atlas Liver Hepatocellular Carcinoma data were performed. Clinical validation, functional assays, rescue experiments, in vivo xenografts, and molecular docking were conducted.

Results

CYP19A1 was identified as a prognostic hub in HCC, with overexpression correlating with advanced T/BCLC stages (p < 0.05) and poor survival (log-rank p < 0.05). Gene set enrichment analysis linked CYP19A1 to dysregulated lipid metabolism, pro-tumorigenic signaling, and immune infiltration. GPER1 was found to be a critical effector of CYP19A1, mediating its effects on proliferation, migration, invasion, epithelial–mesenchymal transition, and protein kinase B activation. CYP19A1 knockdown reduced tumor burden in vivo, whereas GPER1 overexpression rescued this phenotype.

Conclusion

The CYP19A1-GPER1 axis represents a critical oncogenic driver in HCC, providing a mechanistic insight to guide future therapeutic development.