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Identifying critical drivers of oncogenesis and tumor progression is essential for developing effective hepatocellular carcinoma (HCC) therapeutics. Our recent findings has demonstrated that targeting Ephrin Receptor A2 (EPHA2) suppresses HCC initiation and progression by dual inhibition of the Protein Kinase B (AKT) and Signal Transducer and Activator of Transcription 3 (STAT3) signaling.