Neurite outgrowth inhibitor-B (Nogo-B) in physiology and disease.

Nogo-B is an endoplasmic reticulum (ER) membrane-associated protein implicated in both physiological and pathological processes, particularly those that occur within blood vessels, highly vascularized tissues, and involve inflammatory and metabolic responses. Belonging to the reticulon gene family, Nogo-B is predominantly localized to the ER and is characterized by a unique structure and membrane topology. Nogo-B‘s broad expression profile across multiple tissues and organs enables it to regulate numerous physiological functions and evoke responses to disease across eukaryotic organisms. Structurally, Nogo-B can interact with two key transmembrane receptors via distinct domains: its N-terminus binds to the neurite outgrowth inhibitor B receptor (NgBR), while the hydrophilic loop region (Nogo-66) interacts with the Nogo-66 receptor (NgR). These receptors are notably expressed in different tissues, in particular, the cardiovascular, respiratory and renal systems, reflecting the functional relevance of Nogo-B in these organ systems. Additionally, Nogo-B inhibits serine palmitoyl transferase (SPT), the rate-limiting enzyme in the de novo synthesis of sphingosine-1-phosphate (S1P), which is an important modulator of G-protein coupled receptor activity. This review examines the essential role of signaling interactions between Nogo-B and its downstream targets, highlighting their roles in maintaining physiological homeostasis and in disease states, such as cardiovascular, pulmonary and renal diseases, as well as inflammation, glucose and lipid metabolism, fibrosis, and cancer. We also address current controversies and outline future research directions, with a particular focus on the therapeutic potential of targeting Nogo-B signaling across various pathological contexts.