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

Abstract 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.