In conclusion, our study has provided convincing evidence that SENP6 exerts as a SUMO‐specific isopeptidase to induce Nrf2 deSUMOylation, thereby upregulating its ubiquitination modification and promoting its degradation via the ubiquitin proteasome system, resulting in inhibiting the Nrf2‐dependent antioxidant response, ultimately leading to oxidative stress and neuronal death after ischemic stroke. Here, NFE2L2 is linked to ischemic stroke.