Nrf2/SLC7A11/GPX4 pathway, a potential target of oridonin in inhibiting ferroptosis during cerebral ischemia-reperfusion injury progression

Oridonin, the primary bioactive compound in Rabdosia rubescens, has garnered significant attention in recent years. The objective of the current study is to assess the anti-ferroptosis role and possible mechanism of oridonin in cerebral ischemia-reperfusion injury (CIRI). To explore the effects of oridonin on CIRI, we established two experimental models. In vivo, a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) was constructed. In vitro, a model of oxygen-glucose deprivation/reoxygenation (OGD/R) was established using PC12 cells. The administration of oridonin could effectively restore cerebral blood flow, attenuate neuronal injury and reduce infarction area in a rat model of MCAO/R. Oridonin activated Nrf2/SLC7A11/GPX4 pathway and inhibited ferroptosis both in vivo and in vitro. Silencing of Nrf2 significantly reversed the regulatory effect of oridonin on CIRI both in vivo and in vitro. Oridonin is a promising compound to exert neurorestorative effect in CIRI. Activation of Nrf2/SLC7A11/GPX4 pathway contributes to oridonin’s anti-ferroptosis effect. This pre-clinical work may offer insight into developing new mechanisms in the management of CIRI in the future.