Neuroprotective effect of emodin on Aβ25-35-induced cytotoxicity in PC12 cells involves Nrf2/GPX4 and TLR4/p-NF-κB/NLRP3 pathways

[Display omitted] •Emodin ameliorated the cell viability harmed by Aβ25-35.•Emodin relieved the MMP decline, reduced ROS release, and decreased MDA but improved CAT and GSH-Px activity.•Emodin bound to Fe2+ via phenolic hydroxyl groups to decrease free Fe2+.•Emodin upregulated Nrf2/GPX4 pathway to exert an antioxidant and anti-ferroptotic effect.•Emodin downregulated TLR4/p-NF-κB/NLRP3 pathway to exert an antiinflammatory effect. The present study aims to investigate the neuroprotective effects of emodin in Alzheimer’s disease (AD). PC12 cells were used to explore the underlying mechanism and were incubated with Aβ25-35 for 24 h as the model group, incubated with emodin at different concentrations (2.5, 5, 10 μM) as the drug administration groups. The content of MDA and the enzymic activities of CAT, GSH-Px were detected by the corresponding commercial kits. The ROS level in Aβ25-35 induced cells was decreased by emodin dose-dependently, but the MMP in these cells were elevated. The expressions of AChE, TLR4, p-NF-κB, NLRP3, IL-1β, and TNF-α in PC12 cells were increased by Aβ25-35 treatment, the expressions of Nrf2, HO-1, GPX4, xCT were decreased, all the levels of expressions were reversed by emodin. Besides, ultraviolet spectrophotometry and infrared spectrophotometry were ultilized to ascertain the production of emodin-Fe (Ⅱ) complex. The FerroOrange results showed that emodin reduced free Fe2+ in cells. The immunofluorescent intensities of Nrf2, GPX4, and p-NF-κB offered direct visible evidence for emodin’s multi-targets in AD treatment. Collectively, emodin could inhibit the activity of AChE and exert neuroprotective effects against AD through antioxidant, anti-ferroptotic, anti-inflammatory properties via Nrf2/GPX4 and TLR4/p-NF-κB/NLRP3 pathways.