Adipocyte fatty acid‐binding protein as a cerebrospinal fluid–accessible biomarker and druggable target in subarachnoid haemorrhage: Linking fatty acid dysregulation to microglial neuroinflammation

Abstract Background Subarachnoid haemorrhage (SAH), a devastating subtype of stroke, is predominantly caused by the rupture of intracranial aneurysms. Emerging evidence indicates that the risk of intracranial aneurysm rupture correlates with elevated serum levels of fatty acids and pro‐inflammatory cytokines. Moreover, increased serum concentrations of adipocyte fatty acid‐binding protein (A‐FABP), an inflammation‐related adipokine, have been associated with poorer prognosis in SAH. However, the precise roles of A‐FABP in SAH pathogenesis and its biomarker potential in cerebrospinal fluid (CSF) remain unclear. Methods CSF from 40 SAH patients and 30 controls was analysed by targeted fatty acid metabolomics. Experimental SAH mice were induced by endovascular perforation in both genetic deletion and pharmacological inhibition of A‐FABP. Brain injury was quantified by neurobehavioural test, inflammatory cytokine expression and TUNEL staining. In vitro, conditioned medium from fatty acid‐stimulated microglia was applied to primary neurons to evaluate apoptosis. Microglial metabolic reprogramming was assayed with Seahorse XF assays. Results CSF revealed significant metabolic disruption in SAH, characterized by arachidonic acid (AA), linoleic acid and palmitic acid (PA). Enrichment analysis implicated A‐FABP plays a crucial role in SAH pathogenesis. Notably, elevated A‐FABP levels independently predicted increased SAH severity and poorer prognosis. In mice model of SAH, A‐FABP was significantly upregulated in microglia. Genetic deletion and pharmacological inhibition of A‐FABP significantly ameliorated brain injury, including neurological deficits, neuroinflammation and neuronal apoptosis. Mechanistically, PA and AA promoted BV2 microglial inflammation via an A‐FABP‐dependent manner, subsequently inducing apoptosis in co‐cultured primary neurons. Moreover, A‐FABP inhibition reprogrammed microglial metabolism, enhancing fatty acid β‐oxidation and energy supply. Proteomics further identified the JAK2/STAT3 as a downstream pathway of A‐FABP‐mediated neuroinflammation. Conclusions A‐FABP is a promising biomarker and translatable therapeutic target to improve SAH outcome. Targeting A‐FABP disrupts fatty acids–driven neuroinflammation and microglial metabolic reprogramming to reduce brain injury after SAH.