RTN4 (reticulon 4), also known as Nogo, is a multifunctional endoplasmic reticulum (ER) membrane protein that regulates ER morphology, cellular signaling, and neuronal function. Structurally, RTN4 contains a hairpin topology and localizes predominantly to tubular ER regions, where it stabilizes highly curved ER membrane tubules through interactions with DP1/Yop1p 1. RTN4 acts as a crucial regulator of ER-plasma membrane (ER-PM) contact sites; polarization of RTN4-rich curved ER at the cell front versus CLIMP63-rich flattened ER at the back creates an ER-PM contact gradient that confines receptor signaling to the front and directs cell migration 2. The protein regulates ER luminal transport by modulating ER tubule diameter, controlling Ca2+ release and neuronal regeneration 3. RTN4 suppresses angiogenesis and neural repair after cerebral infarction through S1PR2-mediated vascular autophagy enhancement 4, while RTN4 degradation by proteasome triggers pyroptosis in cancer cells through ER membrane remodeling and PKM2-dependent GSDME cleavage, suggesting therapeutic potential in anticancer immunotherapy 5. RTN4 receptors serve as high-affinity ligands for brain-enriched angiogenesis inhibitor (BAI) adhesion-GPCRs, regulating dendritic arborization, axonal elongation, and synapse formation 6. Additionally, RTN4 drives feeding behavior by controlling lipid metabolism in AgRP neurons 7, and induces apoptosis in cancer cells while suppressing tumor development 8.