Fatty acid-binding protein 4 drives neuroinflammation after intracerebral hemorrhage

As key immune sentinels of the central nervous system (CNS), microglia rapidly respond to acute brain injury and engage in dynamic crosstalk with infiltrating peripheral immune cells, collectively shaping the neuroinflammatory milieu—a critical factor governing mortality and long-term functional deficits after intracerebral hemorrhage (ICH). However, the underlying molecular regulatory mechanisms of microglial pathogenic activities remain elusive. Fatty acid-binding protein 4 (FABP4), a metabolic disorder-associated adipokine, have been recognized as a key modulator in inflammatory response. In our study, clinical analyses in ICH patients demonstrated a significant positive correlation between elevated serum FABP4 levels and unfavorable neurological outcomes. Moreover, microglial Fabp4 knockout resulted in attenuated neuronal loss, mitigated cerebral edema, and improved functional recovery after ICH in mice. Mechanistically, increased FABP4 not only promoted lipid droplet deposition, but also inhibited the ubiquitin-proteasome degradation of S100A9 in microglia, synergistically amplifying neuroinflammatory responses. Interestingly, microglial FABP4 also facilitated peripheral neutrophil transendothelial migration into brain parenchyma, and exacerbated brain injury through neutrophil extracellular trap release. Notably, pharmacological inhibition of FABP4 using brain-targeted nanoparticles demonstrated substantial neuroprotective effects in ICH models. These results collectively establish a novel role of FABP4 in orchestrating brain inflammation after ICH and could be targeted to improve neurological outcome.