Abstract Ephrins and Eph family proteins are key intercellular signaling molecules in the nervous system. They regulate processes such as neural development, synaptic plasticity, neural stem cell differentiation, as well as neurodegenerative diseases and neural injury repair through a unique bidirectional signaling mechanism. In recent years, with the deepening of research, the central role of Ephrin and Eph family proteins in the field of neuroscience has gradually emerged, making them a hot topic of study. The purpose of this review is to systematically explore the mechanisms of action of Ephrin and Eph family proteins and their pathways in the nervous system, revealing their critical roles in neural development, functional maintenance, and disease occurrence, while providing theoretical foundations and potential targets for the treatment of neurological disorders. The Ephrin–Eph signaling pathway plays an important role in processes such as neuronal migration, axon guidance, synapse formation and plasticity, and neural stem cell differentiation through a bidirectional signaling mechanism. Abnormalities in this pathway are closely related to the development of neurodegenerative diseases (such as Alzheimer’s disease), impairments in neural injury repair, and the progression of neurological tumors. Increasing evidence highlights the core regulatory position and functional complexity of Ephrin and Eph family proteins in the processes of neural injury and repair. The review also discusses the key regulatory roles of Ephrin and Eph family proteins in neuronal migration and positioning, axon guidance, synapse formation and plasticity, as well as their important functions in neural stem cell differentiation, cell adhesion and repulsion balance, and myelin regeneration. Additionally, this review analyzes the emerging roles of Ephrin and Eph family proteins in regulating the inflammatory microenvironment after neural injury, maintaining blood–brain barrier integrity, and facilitating neural function recovery. This review also summarizes the cellular and molecular mechanisms that support these functions, particularly the dynamic regulatory network of Ephrin–Eph bidirectional signaling and its interactions with other signaling pathways, such as Wnt and MAPK. Future research needs to further elucidate the molecular mechanisms of the Ephrin–Eph signaling pathway, develop highly specific small molecule inhibitors, gene therapy, and immunotherapy strategies, and integrate interdisciplinary technologies (such as single-cell multi-omics, optogenetics, and nanotechnology) to promote clinical translation, paving new avenues for precise treatment of neurological diseases.
Ma et al. (2026) studied this question.