ErbB signaling in brain injury regeneration: Pathway interactions and therapeutic potential

The ErbB signaling network has recently emerged as a key modulator of central nervous system responses to injury. This review provides a comprehensive overview of ErbB receptors and their ligands, highlighting canonical and non-canonical signaling mechanisms relevant to brain damage. We explore how ErbB signaling is dynamically regulated following injury and how it orchestrates processes such as neuroinflammation, gliosis, and neural repair. Special attention is given to its interplay with other critical pathways, including Notch signaling, and its roles within adult neurogenic niches, where it modulates neural stem cell behavior in response to damage. Based on accumulating preclinical evidence, we propose two therapeutic strategies for targeting ErbB signaling in brain injury: (1) dampening neuroinflammation through ErbB inhibition and (2) promoting neuroprotection and neurogenesis via neuregulin-1-mediated activation. The first strategy is supported by studies, which demonstrate that inhibition of ErbB1 limits neuroinflammation and supports neural repair in preclinical models. The latter strategy is supported by emerging studies demonstrating the significant potential of novel protein kinase C activating diterpenes in modulating ErbB signaling pathways through the regulation of neuregulin-1 release. Diterpenes, by influencing the ErbB pathway, may uniquely bridge the gap between neuroprotection and regeneration. Their potential to modulate inflammation and promote pro-regenerative cellular environments positions them as promising tools in the development of targeted therapies. By dissecting these mechanisms, we aim to shed light on the translational potential of ErbB-targeted therapies and their capacity to enhance endogenous repair processes in the injured brain.