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Rationale: Given the crucial role of the Nrf2 pathway in cellular adaptability to stress, targeting small-molecule activation of Nrf2 represents a promising therapeutic strategy for acute ischemic stroke (AIS). However, the clinical translation of existing Nrf2 activators is hindered by adverse effects, such as liver damage, and none are currently approved for AIS. Therefore, we aimed to develop a novel Nrf2 activator that specifically activates neuronal Nrf2 while mitigating adverse effects, with the goal of providing a lead compound for AIS. Methods: We validated the anti-AIS effects and mitochondrial protective functions of the novel Nrf2 activator Cpd.51 through multiple in vivo and in vitro experiments. Mechanistic studies involving surface plasmon resonance, cellular thermal shift assay, co-immunoprecipitation, chromatin immunoprecipitation, GST pull-down, and RNA sequencing were used to determine how Cpd.51 activates Nrf2. A comparative toxicological evaluation was conducted to demonstrate its superior safety profile over parent compound (Omaveloxolone). Results: Cpd.51 exhibited favorable blood-brain barrier permeability, improved safety profile, enhanced mitochondrial function protection and significant neuroprotective effect through the specific activation of neuronal Nrf2. Mechanistically, Cpd.51 interacted with Cys151 and Gly148 in the BTB domain of Keap1, inhibiting Nrf2 degradation, consequently suppressing the transcription of its downstream target DHRS3, a member of the short-chain dehydrogenase/reductase family. Furthermore, Cpd.51 exerted additional Nrf2-activating activity by disrupting protein-protein interactions between Nrf2 and DHRS3. Conclusions: Our work identified Cpd.51 as a novel and safe Nrf2 activator and unveils a unique feedback mechanism involving Nrf2-DHRS3 interaction, providing a new therapeutic avenue for AIS.