Cyclovirobuxine inhibits ferroptosis to mitigate Alzheimer’s disease in glutamate-induced SH-SY5Y cell: the role of the liquid-liquid phase separation of FTH1

Ferroptosis represents a distinct form of cell death that differentiates it from conventional apoptosis. Numerous studies have demonstrated that ferroptosis holds significant potential for elucidating neuronal damage in Alzheimer disease (AD). In addition, liquid-liquid phase separation has emerged as a significant biological process in recent years. It plays a crucial role in the regulation of various proteins in vivo and is closely associated with ferroptosis. Meanwhile, nuclear factor erythroid 2-related factor 2 (Nrf2) serves as a crucial signaling pathway in ferroptosis and plays a significant role in regulating many key components of the ferroptosis pathway. In addition, an increasing volume of research is being conducted on natural medicines aimed at enhancing the treatment of AD. Cyclovirobuxine (Cyc) is an alkaloid compound extracted from the traditional Chinese medicinal plant, boxwood. It has demonstrated therapeutic potential in the treatment of neurodegenerative diseases. Therefore, in this study, we established an AD cell model using glutamate-induced SH-SY5Y. In glutamate-induced SH-SY5Y cells, Cyc treatment significantly improved mitochondrial function and effectively inhibited lipid peroxidation and restored the downregulation of FTH1 levels induced. Furthermore, Cyc treatment activated the Nrf2 signaling pathway, significantly elevated the nuclear levels of Nrf2, and inhibited both iron deposition and lipid peroxidation. Cyc treatment conferred resistance to ferroptosis in erastin-stimulated SH-SY5Y cells, wherein the Nrf2 signaling pathway and FTH1 protein play crucial roles. The collective findings presented here underscore the protective mechanism of action of Cyc in AD and emphasize its potential as a therapeutic agent for AD treatment. SIGNIFICANCE STATEMENT: It reveals at the cellular level the mechanism by which cyclovirobuxine improves Alzheimer disease through the inhibition of ferroptosis, providing a novel approach and strategy for the treatment of patients with Alzheimer disease.