Gastrodin inhibits reactive astrocyte-mediated inflammation in hypoxic-ischemic brain damage through S100B/RAGE-Smad3 signaling

• Gastrodin suppresses reactive astrocyte-mediated neuroinflammation in hypoxic-ischemic brain damage by modulating the S100B/RAGE-Smad3 signaling pathway. • Gastrodin shifts astrocyte polarization from neurotoxic A1 to neuroprotective A2 phenotype, as evidenced by decreased C3 and increased S100A10 and BDNF expression. • The combination of gastrodin with the RAGE inhibitor FPS-ZM1 further reduces A1 astrocyte marker C3, suggesting a potential synergistic therapeutic strategy. • These findings provide a molecular basis for gastrodin as a promising candidate for treating neonatal hypoxic-ischemic brain injury.