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Recent studies have indicated that suppressing oxidative stress and fe rroptosis can considerably improve the prognosis of intracerebral hemorrhage（ICH）.Withaferin A（WFA）,a natural compound,exhibits a positive effect on a number of neurological diseases.Howeve r,the effects of W FA on oxidative stress and ferro ptosis-mediated signaling pathways to ICH remain unknown.In this study,we investigated the neuroprotective effects and underlying mechanism for WFA in the regulation of ICH-induced oxidative stress and ferro ptosis.We established a mouse model of ICH by injection of autologous tail artery blood into the caudate nucleus and an in vitro cell model of hemin-induced ICH.WFA was injected intracerebroventricularly at 0.1,1 or 5 μg/kg once daily for 7 days,starting immediately after ICH operation.WFA markedly reduced brain tissue injury and iron deposition and improved neurological function in a dose-dependent manner 7 days after cerebral hemorrhage.Through in vitro experiments,cell viability test showed that WFA protected SH-SY5 Y neuronal cells against hemininduced cell injury.Enzyme-linked immunosorbent assays in vitro and in vivo showed that W FA markedly decreased the level of malondialdehyde,an oxidative stress marker,and increased the activities of anti-oxidative stress markers supe roxide dismutase and glutathione peroxidase after ICH.Western blot assay,quantitative polymerase chain reaction and immunofluorescence results demonstrated that WFA activated the nuclear factor E2-related factor 2（N rf2）/heme oxygenase-1（HO-1） signaling axis,promoted translocation of N rf2 from the cytoplasm to nucleus,and increased HO-1 expression.Silencing N rf2 with siRNA completely reversed HO-1 expression,oxidative stress and protective effects of W FA.Furthermore,WFA reduced hemin-induced ferroptosis.Howeve r,after treatment with an HO-1 inhibitor,the neuroprotective effects of WFA against hemin-induced ferroptosis were weakened.MTT test res ults showed that WFA combined with ferrostatin-1 reduced hemin-induced SH-SY5 Y neuronal cell injury.Our findings reveal that WFA treatment alleviated ICH injury-induced ferro ptosis and oxidative stress through activating the N rf2/HO-1 pathway,which may highlight a potential role of WFA for the treatment of ICH.