Neuropilin-1: A critical regulator and potential therapeutic target in fibrotic diseases

Fibrosis is a chronic and progressive pathologic condition. Neuropilin-1 (NRP1) is a transmembrane non-tyrosine-kinase glycoprotein receptor. It has emerged as a key regulator of progressive fibrosis through binding to diverse ligands including SEMA3, VEGF, TGF-β, and PDGF. A large amount of evidence suggests that NRP1 is responsible for fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis, and renal fibrosis. NRP1 induces pulmonary fibrosis mainly via the TGF-β1/Smad2/3, TGF-β1-NRP1, PDGFRα/NRP1, and SEMA3B/NRP1/plexin signaling pathways. However, the expression of SEMA3B and NRP1 is reduced in the lung tissues of pulmonary fibrosis mouse models. NRP1 triggers the development of renal fibrosis via multiple pathways such as NRP1/RACK1, SEMA3A/NRP1/plexin, and TGF-β1/Smad3 signaling. Conversely, miR-128-3p/NRP1 may potentially postpone the progression of acute kidney injury. NRP1 participates in the development of hepatic fibrosis by activating hepatic stellate cells. In this review, we focus on the current understanding of NRP1, including its structure, subcellular localization, ligand-receptor interactions, and tissue distribution. We also review the roles of NRP1 in different fibrotic diseases, highlighting its regulatory mechanism. Finally, we present several compounds targeting NRP1 and explore their anti-fibrotic effects. In summary, our review indicates that NRP1 is a potential therapeutic target for fibrotic diseases.