HBEGF (heparin-binding EGF-like growth factor) is a multifunctional growth factor that mediates cellular responses through EGFR, ERBB2, and ERBB4 receptor activation. The protein exists as both a membrane-anchored precursor and a soluble mature form processed proteolytically from the transmembrane version 1. HBEGF functions as a potent mitogen and chemotactic factor for fibroblasts and smooth muscle cells, but notably not for endothelial cells, with higher EGFR binding affinity than EGF itself 1. The growth factor plays critical roles in tissue repair and regeneration, with astrocyte-produced HBEGF demonstrating anti-inflammatory and tissue-protective effects during CNS autoimmunity 2. In spinal cord injury, HBEGF acts as a neurogenic factor necessary for regeneration, with ependymal cells producing it upon injury to facilitate neuron production and tissue bridging 3. Clinically, HBEGF has significant disease relevance across multiple pathologies. It mediates breast cancer metastasis to the brain by facilitating blood-brain barrier crossing 4 and drives ovarian cancer progression through an EGFR-FAK signaling axis 5. In gastric cancer, HBEGF serves as a resistance factor for cetuximab therapy 6. Therapeutically, HBEGF shows promise in neurological disorders, improving cognitive outcomes in anti-NMDAR encephalitis through EGFR pathway activation 7.