Multifunctionality of tissue inhibitor of metalloproteinase-1 in central nervous system diseases

Central nervous system (CNS) diseases are characterized by high morbidity, long disease courses, and irreversible neurological impairment, often resulting from damage to the neurovascular unit (NVU). Tissue inhibitor of metalloproteinase-1 (TIMP-1), the endogenous inhibitor of matrix metalloproteinase-9 (MMP-9), plays a pivotal role in maintaining extracellular matrix (ECM) homeostasis and regulating NVU integrity. Beyond its canonical MMP-inhibitory function, TIMP-1 exerts a wide spectrum of MMP-independent effects as a multifunctional cytokine that interacts with cell surface receptors such as CD63/β1-integrin and low-density lipoprotein receptor-related protein-1 (LRP-1). Through activation of FAK/PI3K-Akt and MAPK signaling pathways, TIMP-1 modulates astrocyte proliferation, neural stem cell adhesion and migration, endothelial barrier stability, and myelin regeneration. Altered TIMP-1 expression is closely associated with the onset, progression, and prognosis of major CNS disorders, including ischemic stroke, epilepsy, multiple sclerosis, and neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Accumulating evidence highlights its dual, context-dependent roles-protective in acute neuroinflammatory and ischemic injury, yet potentially profibrotic or maladaptive under chronic pathological conditions. This review comprehensively summarizes recent advances in understanding the molecular mechanisms and biological functions of TIMP-1 in CNS diseases, emphasizing its regulatory networks in neuroinflammation, neuroprotection, and neuroregeneration. A deeper understanding of TIMP-1 signaling dynamics will accelerate its translational application as a diagnostic biomarker and therapeutic target for restoring neurovascular unit function in CNS disorders.