HY-021068 improves neuronal ferroptosis by activating Nrf2 signaling in APP/PS1 Mice and Aβ_1-42-induced HT22 cells

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with an unclear pathogenesis and no effective treatment methods. HY-021068 (HY), a novel class I drug, exhibits significant neuroprotective properties in ischemic brain injury. Recent studies suggest that neuronal ferroptosis may be a critical contributor to the onset and progression of AD. However, it is still unclear whether HY treatment has protective effects on AD by inhibiting ferroptosis. In this study, APP/PS1 double transgenic mice were used to investigate the effect and mechanism of HY in AD. In vitro, HT22 cells were stimulated with Amyloid β_1-42 (Aβ_1-42) (5 μM) to elucidate the therapeutic effect of HY and its potential mechanism. The present study indicated that HY treatment significantly improved cognitive dysfunction, enhanced synaptic integrity by upregulating PSD95 and Synapsin I, and reduced Aβ plaque load, APP, beta-secretase 1 (BACE1) expression, and Tau hyperphosphorylation. Furthermore, HY increased glutathione peroxidase 4 (Gpx4) and Cystine/glutamate transporter (xCT) levels, while reduced DMT1 and transferrin receptor expression, eventually inhibiting neuronal ferroptosis. Mechanistically, HY decreased reactive oxygen species (ROS) accumulation and activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by elevating Nrf2, heme oxygenase 1 (HO1), and NAD(P)H quinone oxidoreductase 1 (NQO1) expression. The in vitro study also suggested that the Nrf2 inhibitor ML385 markedly diminished the protective effects of HY, while the Nrf2 activator dimethyl fumarate (DMF) resulted in a significant enhancement of HY's therapeutic effects in Aβ_1-42-induced HT22 cells. Molecular docking and cellular thermal shift assay showed that HY had an interaction with Nrf2. These results suggested that HY could ameliorate AD-related cognitive decline and neuronal ferroptosis through activating Nrf2 pathway, positioning it as a promising therapeutic strategy for AD.