Xiong Liu, Cheng Cao, Ningbo Xu, Feng Xu, Lei Huang, Prativa Sherchan, Desislava Doycheva, John H. Zhang, Jiping Tang, Jerry Flores, Xionghui Chen
Germinal matrix hemorrhage (GMH) is a common form of neonatal stroke in preterm infants and often results in severe and lasting neurological deficits. Persistent hematoma is a key contributor to secondary brain injury. In this study, we investigated the therapeutic potential of niacin in promoting hematoma clearance and neuroprotection after GMH. We found that intranasal administration of niacin markedly improved neurological function, accelerated hematoma clearance, and attenuated secondary brain damage in neonatal rats. Mechanistically, niacin activated HCAR2(hydroxycarboxylic acid receptor 2) and further upregulated its expression, inducing microglial polarization toward the M2 phenotype through the SIRT1/Nrf2 pathway. This activation enhanced CD36/CD163/HO-1-mediated phagocytosis and degradation of erythrocytes and hemoglobin. Nuclear translocation of Nrf2 is essential for the effects of niacin. CRISPR-mediated knockout of HCAR2, or pharmacological inhibition of SIRT1 or Nrf2, abolished niacin-induced hematoma clearance and neuroprotection. Furthermore, microglial depletion significantly attenuated the protective effects of niacin. Collectively, niacin regulates microglial function via the HCAR2/SIRT1/Nrf2 signaling axis to reduce neuronal damage, neuroinflammation, and oxidative stress, thereby alleviating hydrocephalus and improving neurological outcomes. These findings suggest a potential non-invasive therapeutic strategy for neonatal GMH.