Abstract: The central nervous system (CNS) does not function in isolation—it engages in continuous molecular dialogue with the vascular and immune systems. Traditionally, the blood-brain barrier (BBB) was portrayed solely as an impermeable wall, safeguarding the CNS by excluding blood–derived molecules and circulating cells. However, this view has evolved. The BBB is now recognized as a dynamic interface that selectively regulates the exchange of signals, cells, and molecules between the bloodstream and the CNS to maintain a homeostatic neurovascular environment. “BBB breakdown” thus refers not only to the physical deterioration of cell-to-cell junctions but also to alterations in transport mechanisms and transcytotic pathways that increase vascular permeability. When this finely tuned balance is disrupted, the influx of neurotoxic blood proteins and immune cells transforms the stable neurovascular niche into a proinflammatory environment, triggering processes that initiate and accelerate the progression of neurological diseases (Akassoglou et al., 2024). These blood-derived factors act as upstream triggers of neuroinflammation, activating microglia, the resident immune cells of the brain, which further damage the BBB and the surrounding brain tissue. This bidirectional interplay reinforces a pathological cycle of inflammation and barrier compromise, propagating neural injury in a spectrum of CNS diseases from development through aging. Among these factors, fibrinogen has emerged as a central molecular orchestrator of neurovascular pathology (Petersen et al., 2018). Beyond its classical role in coagulation, growing evidence shows that fibrinogen is a key driver of neuroinflammatory responses and a regulator of CNS stem and progenitor cells, suppressing regenerative signaling pathways and impairing both brain development and repair (Nath et al., 2024; Ryu et al., 2024; Weaver et al., 2024). These insights shift our understanding of blood–brain interactions from secondary consequences of neurological disease to active barriers to regeneration, highlighting new targets for therapeutic intervention to promote CNS repair.