NRG1 (neuregulin 1) is a ligand that directly activates ERBB3 and ERBB4 receptor tyrosine kinases, recruiting ERBB1 and ERBB2 as coreceptors to trigger phosphorylation and downstream signaling cascades. NRG1 binding to integrins is essential for optimal ERBB3 signaling, activating MAPK3/ERK1, MAPK1/ERK2, and AKT1 pathways 1. The protein regulates diverse physiological processes including neuromuscular junction formation, cardiac development, and neural differentiation 2. Clinically, NRG1 gene fusions function as oncogenic drivers in solid tumors, particularly in invasive mucinous adenocarcinomas of the lung (10-30% incidence) and pancreatic ductal adenocarcinoma 3. NRG1 fusions promote tumorigenesis through aberrant ERBB pathway activation 4. Additionally, NRG1 secreted by cancer-associated fibroblasts mediates paracrine tumor support mechanisms, enabling antiandrogen resistance in prostate cancer and facilitating KRAS inhibitor bypass in pancreatic cancer through HER3 activation 56. In breast cancer, NRG1-HER3 signaling drives circulating tumor cell survival and therapy resistance, with compensatory FGFR1 signaling providing plasticity 7. The bispecific antibody zenocutuzumab targeting HER2 and HER3 simultaneously has demonstrated clinical efficacy in NRG1 fusion-positive cancers and received FDA approval in 2024 for advanced pancreatic adenocarcinoma and NSCLC 84.