NXPZ-2 is an orally active Keap1-Nrf2 protein–protein interaction (PPI) inhibitor with a K i value of 95 nM, EC 50 value of 120 and 170 nM. NXPZ-2 can dose-dependently ameliorate Aβ-Induced cognitive dysfunction , improve brain tissue pathological changes in Alzheimer’s disease (AD) mouse by increasing neuron quantity and function. NXPZ-2 can inhibit oxidative stress by increasing Nrf2 expression levels and promoting its cytoplasm to nuclear translocation, which is helpful for Keap1-Nrf2 PPI inhibitors and AD associated disease research.