SEMA3E (semaphorin 3E) is a secreted ligand that primarily functions through binding to its receptor Plexin-D1, independent of neuropilins 1. The SEMA3E-Plexin-D1 axis mediates cytoskeletal reorganization and cell retraction, playing critical roles in vascular patterning and angiogenesis regulation during embryogenesis and postnatal development 1. In pathological contexts, SEMA3E has emerged as a significant contributor to fibrotic diseases. In idiopathic pulmonary fibrosis (IPF), Furin-mediated cleavage of full-length P87-SEMA3E into bioactive P61-SEMA3E drives fibroblast activation, proliferation, and migration through ErbB2 phosphorylation 2. Elevated plasma SEMA3E levels in IPF patients negatively correlate with lung function 2. Beyond fibrosis, SEMA3E participates in macrophage-fibroblast crosstalk during organ injury-induced fibrosis 3 and is implicated in endometrial pathology, where aberrant SEMA3 signaling contributes to thin endometrium through compromised stromal cell proliferation 4. SEMA3E also functions in epileptogenesis, with elevated plasma levels correlating with seizure frequency and enriched expression in excitatory neurons 5. Additionally, SEMA3E represents an upregulated pro-inflammatory marker in type 2 diabetes mellitus 6. These findings position SEMA3E as a multifunctional pathogenic mediator with therapeutic potential across fibrotic, neurological, and metabolic diseases.