Fibrinogen in extracellular matrix remodeling: functional switching, source heterogeneity, and biomaterial translation.

Fibrinogen (FG), which is typically regarded as a circulating coagulation protein, is now supported by growing evidence as also serving as a context-dependent regulator of extracellular matrix (ECM) remodeling during tissue repair, inflammation, fibrosis, cancer progression, and biomaterial-mediated regeneration. In this review, we examine how FG activity is shaped by local concentration, polymerization state, proteolytic processing, post-translational modification, receptor availability, matrix mechanics, and cellular source. Rather than treating FG as a molecule that is uniformly reparative or pathogenic, we outline a functional-switching model wherein transient FG deposition and selected FG-derived fragments may support epithelial repair, endothelial barrier stabilization, regeneration, and immune resolution, whereas persistent FG/FN-rich matrices, excessive proteolysis, inflammatory receptor engagement, and altered mechanical cues are associated with chronic inflammation, fibrosis, vascular leakage, and tumor-supportive remodeling. We also consider source heterogeneity, through which systemic hepatocyte-derived FG is distinguished from locally produced or ectopically deposited FG in specialized tissue niches. Current evidence, which supports hepatocytes as the main source of circulating FG, also suggests that extrahepatic sources, including epithelial, endothelial, and tumor-associated cells, may influence local ECM behavior under disease-specific contexts. By contrast, the possibility of macrophage-derived FG remains unresolved, a situation that requires both transcript- and protein-level validation. Finally, we relate these biological principles to fragment-guided therapeutic design, receptor-selective blockade, source-aware targeting, and stimulus-responsive FG-based biomaterials, emphasizing that biomaterial translation should not simply incorporate FG as a passive scaffold but should instead program material stiffness, degradation kinetics, ligand exposure, and local fragment generation so that reparative signaling is favored while persistent inflammatory or fibrotic matrices are avoided. It is upon FG fragmentomics, spatial multi-omics, tunable biomaterial platforms, and lineage-resolved validation that future progress will depend, as these approaches will define when FG supports repair and when it contributes to pathological remodeling.