ESRRA-Driven PHF5A Activation Promotes Hepatocellular Carcinoma Progression and is Therapeutically Targeted by Rosuvastatin

Background The estrogen related receptor alpha (ESRRA), a key member of the estrogen receptor-related receptor (ERR) family, has been extensively implicated in tumor progression across multiple cancers. Existing studies highlight its pivotal role in cancer cell proliferation and migration. However, its specific function and underlying molecular mechanisms in hepatocellular carcinoma (HCC) remain incompletely understood. Methods The effects of ESRRA on HCC cells proliferation and migration were investigated in vitro (CCK-8, colony formation, EdU proliferation, wound-healing, transwell assays, and Epithelial-mesenchymal transition (EMT) marker analysis) and in vivo (Balb/c nude mouse subcutaneous xenograft and lung metastasis models). RNA sequencing and dual-luciferase reporter assays were employed to identify ESRRA’s downstream targets and pathways. Results ESRRA promoted HCC cell proliferation and migration in vitro and in vivo . Mechanistically, ESRRA transcriptionally upregulated PHD finger protein 5A (PHF5A), which subsequently activated the PI3K/AKT signaling cascade. The cholesterol-lowering drug rosuvastatin exerted anti-tumor effects on HCC by downregulating ESRRA and, meanwhile, suppressing its transcriptional activity through depleting intracellular cholesterol. Conclusion ESRRA promotes HCC progression via the PHF5A /PI3K/AKT axis and mediates rosuvastatin's anti-tumor effect. Targeting ESRRA-PHF5A may be a therapeutic strategy for HCC.