Broadening the View: Substance P and Its Metabolism in Pruritus‐Related Diseases

Chronic pruritus is a debilitating symptom accompanying numerous inflammatory skin diseases and remains a major therapeutic challenge. Neurogenic inflammation plays a central role in its pathogenesis, with the tachykinin substance P acting as a key mediator at the interface of the nervous system, immune cells, and cutaneous tissues. While substantial research has focused on substance P signaling via the neurokinin-1 receptor, clinical trials targeting this pathway have yielded inconsistent results, suggesting an incomplete understanding of substance P-mediated mechanisms in pruritic disorders. This review broadens the current perspective by highlighting the importance of substance P metabolism and the biological activity of its metabolites in pruritus-related diseases. Many C-terminal substance P metabolites retain neurokinin 1-receptor affinity but induce biased intracellular signaling. In contrast, N-terminal metabolites can activate alternative receptors such as mas-related G protein-coupled receptor X2, promoting mast cell degranulation, neurogenic inflammation, and itch, or exert counter-regulatory effects via yet unidentified targets. Importantly, the expression and activity of substance P-degrading proteases are altered in pruritic skin diseases, shifting the balance toward biologically active, pruritogenic metabolites. In conclusion, substance P, its metabolites, receptor isoforms, and metabolizing enzymes form a complex regulatory network that fine-tunes itch, pain, and inflammatory signaling. A deeper understanding of this interplay may explain the limited efficacy of current therapeutic approaches and might offer novel targeted treatment strategies in chronic pruritus.