PLXND1 (plexin D1) is a cell-surface receptor for semaphorins (particularly SEMA3A, SEMA3C, SEMA3E, and SEMA3D) that regulates cell migration, axon guidance, and vascular development 1. Beyond canonical ligand-binding, PLXND1 functions as a mechanosensor in endothelial cells, forming a mechanocomplex with neuropilin-1 and VEGFR2 to detect shear stress and regulate site-specific atherosclerotic lesion distribution 2. This dual functionality—ligand sensing and mechanosensing—is achieved through distinct molecular conformations of the receptor. Clinically, PLXND1 mutations cause congenital neurodevelopmental disorders; a missense variant (p.V964M) was identified in Poland-Möbius syndrome, implicating PLXND1 in cranial nerve and vasculature development 3. In pathological contexts, PLXND1 contributes to multiple diseases: it mediates perineural invasion and metastasis in pancreatic cancer via SEMA3D signaling 1, promotes neural lineage plasticity in treatment-resistant prostate cancer 4, and drives lung fibrosis through SEMA3E-dependent fibroblast activation 5. High PLXND1 expression associates with poor prognosis in hepatocellular carcinoma and predicts immune infiltration patterns 6. In idiopathic pulmonary fibrosis, PLXND1 acts as a pro-fibrotic driver and endothelial senescence-related gene 7. Emerging evidence suggests PLXND1 participates in retinal inflammation via CD64+ monocyte-RPE crosstalk in age-related macular degeneration 8.