The A-FABP Nexus in the Neurovascular Unit: Bridging Endothelial Barrier Breakdown and Microglial Lipotoxicity in...

Ischemic stroke is a neurological cerebrovascular event characterized by highly complex, spatiotemporally dynamic pathophysiological processes. In recent years, stroke research has shifted from early isolated neuroprotection to the systematic investigation of the multidimensional homeostasis of the entire neurovascular unit (NVU). Within this complex pathological network, neuroinflammation mediated by cerebral lipid metabolic dysregulation has gradually emerged as an important contributor to NVU dysfunction and post-stroke secondary injury. Among various lipid chaperones, adipocyte fatty acid-binding protein (A-FABP) has attracted increasing attention because of its involvement in metabolic dysregulation, vascular injury, and neuroinflammation. This review comprehensively examines the emerging evidence for the multifaceted involvement of A-FABP in ischemic stroke. In the hyperacute phase, A-FABP acts as a potent endothelial disruptor, compromising the integrity of the blood-brain barrier (BBB) by activating MMP-9; Beyond this established vascular mechanism, findings from other experimental contexts suggest that A-FABP may also contribute to microglial lipid dysregulation and associated inflammatory responses, providing a potential mechanistic link between vascular injury and immune-metabolic dysfunction within the NVU. Preclinical studies further indicate that pharmacological inhibition or neutralization of A-FABP can attenuate ischemic brain injury; however, its therapeutic efficacy and safety in patients with ischemic stroke remain to be established. This review provides an in-depth analysis of the dynamic balance of the spatiotemporal effects of A-FABP, further highlighting its core value as a biomarker for poor stroke prognosis and a highly promising therapeutic target. It also examines current translational bottlenecks, including phase-specific intervention windows, applicability across different stroke subtypes, unresolved mechanisms of NVU crosstalk, and pharmacological optimization, aiming to provide directions for future investigation of A-FABP within the stroke immune-metabolic network.