ETV5 improves ischemic stroke by targeting HACE1/Nrf2 axis to inhibit microglia M1 polarization and neuron pyroptosis

Ischemic stroke is a kind of cerebrovascular disease with high mortality. The expression of ETS variant transcription factor 5 (ETV5) is down-regulated in ischemic stroke, but the specific role and mechanism remain unclear. In this study, the effects of ETV5 on ischemic stroke were investigated in vivo and in vitro by establishing the middle cerebral artery occlusion/reperfusion (MCAO/R) animal model and oxygen-glucose deprivation/reoxygenation (OGD/R) microglia model, respectively. We found that ETV5 reduced the infarct size, neurological deficit, microglia M1 polarization, and neuron pyroptosis level. Mechanistically, we further examined the expression of the HECT domain and ankyrin repeat-containing E3 ubiquitin protein ligase 1 (HACE1) and nuclear factor erythroid 2-related factor 2 (Nrf2) based on animal and cellular models to assess whether ETV5 affects ischemic stroke through the HACE1/Nrf2 signaling pathway. We found that ETV5 promoted the expression of HACE1 and Nrf2 in microglia and that HACE1 was transcriptionally activated by ETV5, which in turn competed with the E3 ligase KEAP1 for binding of Nrf2 and enhances the protein stability and nuclear expression of Nrf2. Our results suggest that ETV5 can ameliorate brain injury caused by ischemic stroke and this is closely related to inducing the HACE1/Nrf2 pathway to inhibit microglia M1 polarization.