5-Methoxyseselin inhibits neuronal ferroptosis and β-amyloid production in female APP/PS1 transgenic mice.

Nrf2 signaling dysregulation drives progressive cognitive decline in Alzheimer's disease (AD), as the brain's endogenous defenses fail to neutralize oxidative stress and ferroptotic neuronal attrition. Here, we report that 5-Methoxyseselin (5-Met), a natural coumarin derivative, is a nuclear factor erythroid 2-related factor 2 (Nrf2) inducer that facilitates glutathione peroxidase 4 (GPX4)-mediated lipid-repair machinery. Mechanistically, 5-Met may bind to Kelch-like ECH-associated protein 1 (Keap1), thereby disrupting the Keap1-Nrf2 inhibitory interaction and promoting Nrf2 stabilization. This leads to upregulated GPX4 expression and subsequent suppression of neuronal ferroptosis in APP/PS1 mice. Consistently, 5-Met treatment effectively protected N2a cells from ferroptotic challenges induced by ferric ammonium citrate (FAC), erastin, or RSL3 via upregulating GPX4 expression. Furthermore, 5-Met modulated β-amyloid (Aβ) homeostasis by inhibiting β-amyloid precursor protein-cleaving enzyme 1 (BACE1)-mediated Aβ production and enhancing low-density lipoprotein receptor-related protein 1 (LRP1)-mediated Aβ efflux. In addition, 5-Met treatment improved cognitive performance in APP/PS1 mice. Collectively, these findings identify 5-Met as a multi-target neuroprotective agent that restores Aβ homeostasis and inhibits neuronal ferroptosis, suggesting it may be a therapeutic compound for AD.