Neuropilin‑1: Emerging roles in nerve‑vessel‑bone coupling during fracture repair (Review)

Fracture healing is a sophisticated biological process orchestrated by the spatiotemporal coordination of neural, vascular and skeletal systems to sustain reparative homeostasis. However, this regulatory network is often disrupted in pathological conditions, such as osteoporosis, diabetes and aging, leading to impaired outcomes, such as delayed fracture healing and nonunion. Synthesizing available multidisciplinary evidence suggests that neuropilin‑1 (NRP1), a transmembrane glycoprotein with pleiotropic functions, may serve as a potential mediator integrating multisystemic signals and participating in nerve‑vessel‑bone crosstalk during fracture repair. Endowed with distinctive structural domains, NRP1 selectively binds diverse ligands and has been observed to localize preferentially in active bone repair zones and critical cellular populations. There, it exhibits preliminary biological potential to assist in coordinating angiogenesis, modulating the function of bone‑repair cells, and guiding nerve fibers. In systemic metabolic disorders or in localized, extreme inflammatory microenvironments, dysregulation of NRP1‑mediated signaling may be associated with clinical complications, such as delayed fracture healing and nonunion. Therefore, a more in‑depth exploration of the nerve‑vessel‑bone crosstalk and pathological networks potentially governed by NRP1 may provide preliminary mechanistic insight into the imbalances in bone repair. The present review summarizes the current understanding of the possible roles of NRP1 in physiological fracture healing and organizes reported specific dysregulation patterns across systemic high‑risk diseases and distinct inflammatory osteolytic states. Finally, the present review discusses the translational potential of NRP1 as a candidate therapeutic target for delayed healing, explicitly highlighting current translational opportunities and significant preclinical barriers, in an aim to provide a preliminary theoretical framework for developing NRP1‑targeted therapies for nonunion.