Mechanisms and precision intervention strategies of time-dependent dynamic regulation of matrix metalloproteinase-mediated cerebrovascular barrier disruption and neurovascular unit remodeling in stroke.

Stroke remains a leading cause of global mortality and long-term disability. Despite the clinical success of reperfusion therapies, their efficacy is hampered by narrow therapeutic windows and the risk of secondary brain injury. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, have emerged as pivotal biphasic regulators in the onset, progression, and resolution of ischemic stroke. This review synthesizes current evidence regarding the multifaceted roles of MMPs in stroke pathophysiology. Prior to ictus, MMPs increase vascular vulnerability by driving pathological remodeling in atherosclerosis and hypertension. During the acute phase, the rapid activation of MMP-2, -3, and - 9 degrades tight junction proteins (e.g., occludin, claudin-5, ZO-1) and extracellular matrix (ECM) components, precipitating blood-brain barrier (BBB) disruption, neuroinflammation, and hemorrhagic transformation. Conversely, during the subacute and recovery phases, MMP-2 and MMP-13 facilitate neurovascular unit (NVU) repair by promoting angiogenesis, synaptic plasticity, and ECM remodeling. Furthermore, we highlight the role of aberrant MMP signaling in mediating the brain-peripheral organ axis, which triggers sympathetic imbalance and systemic immune dysfunction. Despite promising preclinical results with small-molecule inhibitors and tissue inhibitors of metalloproteinases (TIMPs), clinical translation has been stifled by the nonspecific toxicity of broad-spectrum inhibitors and the inadvertent suppression of beneficial MMP functions during the repair phase. We conclude that the therapeutic paradigm must shift from broad-spectrum inhibition to precision regulation. Tailoring interventions to specific molecular subtypes, cell types, and temporal windows is essential. This review provides a theoretical framework for developing stage-specific MMP-targeted therapies to improve clinical outcomes in stroke patients.