Simple SummaryThis narrative literature review delves into the role of EPH/ephrin signaling in liver cancer and its implications for tumor progression and potential therapeutic strategies. This review focuses on the relationship between hypoxia and HCC development, highlighting the upregulation of hypoxia-inducible factor 1-alpha (HIF-1α) in HCC cells under low oxygen conditions. It explores the significance of the EPH/ephrin axis in regulating the hypoxic tumor microenvironment (TME) of HCC. The review also highlights the new avenues for therapeutic interventions that open the targeting of the EPH/ephrin signaling pathway in liver cancer treatment by unraveling the significance of the EPH/ephrin signaling.AbstractLiver cancer is a complex and challenging disease with limited treatment options and dismal prognosis. Understanding the underlying molecular mechanisms driving liver cancer progression and metastasis is crucial for developing effective therapeutic strategies. The EPH/ephrin system, which comprises a family of cell surface receptors and their corresponding ligands, has been implicated in the pathogenesis of HCC. This review paper aims to provide an overview of the current understanding of the role of the EPH/ephrin system in HCC. Specifically, we discuss the dysregulation of EPH/ephrin signaling in HCC and its impact on various cellular processes, including cell proliferation, migration, and invasion. Overall, the EPH/ephrin signaling system emerges as a compelling and multifaceted player in liver cancer biology. Elucidating its precise mechanisms and understanding its implications in disease progression and therapeutic responses may pave the way for novel targeted therapies and personalized treatment approaches for liver cancer patients. Further research is warranted to unravel the full potential of the EPH/ephrin system in liver cancer and its clinical translation.