Fibronectin 1 (FN1) is a secreted extracellular matrix protein with multifaceted roles in tissue homeostasis and disease. As an extracellular matrix structural component, FN1 mediates integrin-dependent signaling, particularly through ITGA5:ITGB1 receptors 1. In physiological contexts, FN1 regulates fibrotic responses: profibrotic Spp1-macrophages express high FN1 levels and orchestrate fibroblast activation through FN1-receptor crosstalk after organ injury, with platelets driving this differentiation via CXCL4 2. FN1 degradation via p62/SQSTM1-dependent autophagy-lysosome pathway suppresses epithelial-mesenchymal transition in head and neck cancer, where elevated FN1 correlates with poor prognosis 3. Pathologically, FN1 accumulation promotes chemoresistance in triple-negative breast cancer through FAK/Src signaling activation, whereas LOX inhibition reduces FN1 assembly and restores chemosensitivity 4. In glioblastoma, cancer-associated fibroblast-derived FN1 facilitates tumor cell migration and invasion 1. Conversely, rare FN1 loss-of-function variants protect APOEε4 carriers against Alzheimer's disease by reducing pathological vascular FN1 deposition, gliosis, and improving toxic protein clearance 5. NK cell-mediated IFN-γ production increases FN1 expression, altering tumor architecture and suppressing metastasis 6. Notably, FN1-receptor tyrosine kinase gene fusions occur in calcified chondroid mesenchymal neoplasms 7.