Gastrodin inhibits the dephosphorylation of EGFR by DUSP3 to suppress oxidative stress-induced ferroptosis in astrocytes and alleviate cerebral ischemia-reperfusion injury.

Cerebral ischemia-reperfusion injury (CIRI) poses great challenges for drug development because of its complex pathogenesis. The involvement of astrocytes in the pathogenesis of CIRI has given rise to the development of novel drug strategies that target these cells. This study aims to investigate the effects of gastrodin, the main bioactive component of Gastrodia elata, on astrocytes during CIRI and the molecular mechanism. Gastrodin inhibited oxidative stress (OS) in astrocytes in a concentration-dependent manner and restored the neuroprotection of astrocytes. Gastrodin destabilized dual specificity protein phosphatase 3 (DUSP3) in astrocytes, leading to attenuation of its protein expression, which activated epidermal growth factor receptor (EGFR) phosphorylation and nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase 1 (HO-1) antioxidant signaling. Inhibition of OS by gastrodin ameliorated ferroptosis in astrocytes during CIRI, increased GSH concentration, relieved mitochondrial damage, and reduced Fe content. The ameliorative effects of gastrodin on astrocyte OS and ferroptosis, and CIRI in mice, were reversed by restoring DUSP3 expression or by treatment with the EGFR phosphorylation inhibitor gefitinib. In summary, gastrodin demonstrated ameliorative effects on astrocyte OS and CIRI-induced neurological impairments, which were dependent on the inhibition of DUSP3 expression and EGFR dephosphorylation.