Abstract
Mast cells, characterized by a broad repertoire of surface receptors, are increasingly recognized for activation pathways extending beyond the classical IgE/FcεRI axis, particularly in the context of neurogenic inflammation. Substance P (SP), a neuropeptide of the tachykinin family, is a potent activator of mast cells, inducing the release of histamine, cytokines, and other inflammatory mediators. Through complex bidirectional communication, mast cells and SP play a pivotal role in neuro–immune interactions. This narrative review provides an updated overview of mast cell–SP crosstalk, with a focus on underlying molecular mechanisms, receptor-mediated signaling pathways, and their contribution to pathophysiological processes. In addition, we aim to reinterpret established clinical models within the spectrum of pseudoallergic conditions and to explore innovative, etiology-driven therapeutic strategies. Finally, we discuss future perspectives and highlight the need for robust translational models to support clinical and pharmacological research.