AbstractAimFerroptosis is increasingly becoming to be considered as an important mechanism of pathological cell death during stroke, and specific exogenous ferroptosis inhibitors have the ability to reverse cerebral ischemia/reperfusion injury. However, research on Srs11‐92 (AA9), a ferrostatin‐1 (Fer‐1) analog, in preclinical studies is limited.MethodsIn the middle cerebral artery occlusion‐reperfusion (MCAO/R) mice model or oxygen–glucose deprivation/reperfusion (OGD/R) cell model, Fer‐1, AA9, and/or ML385 were administered, and brain infarct size, neurological deficits, neuronal damage, oxidative stress, and neuroinflammation were determined after the damage, in vitro and in vivo.ResultsFer‐1 and AA9 improved brain infarct size, neuronal damage, and neurological deficits in mice model of MCAO/R, and inhibited the overloaded iron deposition, ROS accumulation, and neuroinflammation response: it also increased the expression of GPx4, Nrf2, and HO‐1 and suppressed the expression of HMGB1 and NF‐κB p65 in the epicenter of injured hippocampal formation. However, Nrf2 inhibitor ML385 reversed the neuroprotective effect of AA9, including the oxidative stress and neuroinflammation. In vitro studies showed that AA9 relieved OGD/R‐induced neuronal oxidative stress and neuroinflammation via the Nrf2 pathway, which was impaired by ML385 in primary neurons.ConclusionThe findings imply that Fer‐1 analog AA9 may be suitable for further translational studies for the protection of neuronal damage via Nrf2 signal pathway‐mediated oxidative stress and neuroinflammation in stroke and others neurological diseases.