Exploring Neuregulin3: From physiology to pathology, a novel target for rational drug design

Neuregulin 3 (NRG3) is an epidermal growth factor related protein that binds to and stimulates the Erb-B2 receptor tyrosine kinase 4 (ErbB4). NRG3 is a multifunctional protein with fifteen alternative splicing isoforms categorized into four classes. Numerous physiological processes, such as the formation of cortical plate, cortical patterning, synaptic development, neuronal proliferation, regulation of neurotransmission, control of impulsive behavior, mammary gland morphogenesis, spermatogonial proliferation and cardiac homeostasis are influenced by NRG3. Besides its physiological roles, NRG3 also modulates anxiogenic phenotypes. It is a susceptibility gene for schizophrenia, autism spectrum disorder and Hirschsprung's Disease. Furthermore, anxiety during nicotine withdrawal is dependent on NRG3-ErbB4 signaling. Research on a range of solid carcinomas, such as brain tumors, ovarian cancer, gastrointestinal cancer and breast cancer, has demonstrated NRG3 gene as a therapeutic target. NRG3 also has potential involvement in epilepsy, angular limb malformation in Rambouillet rams, amyotrophic lateral sclerosis and polythelia. Nevertheless, little is known about the molecular characteristics, activities specific to isoforms, and molecular mechanisms of NRG3. Examining its potential involvement in a range of physiological processes and pathological states is a unique area that needs in-depth study and may offer new mechanistic insights and comprehension of these elements. Thus, the purpose of this review is to shed light on the utility of NRG3 as a potential target in various health and disease conditions.