Noncanonical Signaling Network of Nogo-A: A New Perspective on Multi-target Regulation, Neuroplasticity, and Disease Intervention Beyond NgR

The membrane protein Nogo-A, initially identified for its inhibitory role in axonal regeneration through the Nogo receptor (NgR), is now recognized as a central hub in a complex noncanonical signaling network. Recent evidence indicates that Nogo-A engages diverse receptors and intracellular pathways beyond NgR to modulate neuroplasticity, synaptic stability, and glial function. This multi-target regulatory capacity characterizes Nogo-A as a critical determinant of neural repair and degeneration, with implications for conditions such as spinal cord injury, multiple sclerosis, and Alzheimer’s disease. Noncanonical Nogo-A signaling intersects with growth factor cascades, inflammatory responses, and cytoskeletal dynamics, offering novel therapeutic targets for neural repair. This review synthesizes current knowledge on alternative Nogo-A signaling mechanisms and highlights their potential to redefine strategies for neuroregeneration and disease intervention. Graphical Abstract Noncanonical Nogo-A Signaling Network. This graphical abstract summarizes the Nogo-A signaling network. It illustrates how Nogo-A engages diverse receptors (e.g., PirB, S1PR2) beyond the classical NgR to activate divergent pathways, modulating neuroplasticity and offering novel therapeutic targets for neural repair