Journal of Neuroimmunology · Jul 22, 2025

Fisetin alleviates Aβ-induced neuronal cell ferroptosis by regulating Sirt6-mediated deacetylation modification

By Xie Y, Li C, Zhang Y et al.

BACKGROUND: Ferroptosis contributes to Alzheimer's disease (AD) pathology. Fisetin, a flavonoid with neuroprotective properties, has shown potential in reducing oxidative stress and inflammation. This study investigates the protective effects and underlying molecular pathways of fisetin against amyloid-β (Aβ)-induced ferroptosis in neuronal cells. METHODS: HT22 mouse hippocampal neuronal cells were pre-incubated with fisetin before exposure to amyloid-β (Aβ). Cell viability was evaluated by Cell Counting Kit-8 (CCK-8) assay, and lipid peroxidation was measured with the C11-BODIPY probe. Protein expression patterns were determined via Western blot analysis. Co-immunoprecipitation (CoIP) and ubiquitination assays were used to explore the interactions between Sirtuin 6 (Sirt6), nuclear factor erythroid 2-related factor 2 (Nrf2), and kelch-like ECH-associated protein 1 (Keap1). RESULTS: Fisetin pre-treatment significantly alleviated Aβ-induced ferroptosis in HT22 cells. Sirt6 upregulation was observed following fisetin treatment, and silencing Sirt6 reversed its protective effects on Aβ-induced neuronal cell ferroptosis. Mechanistically, Sirt6 deacetylated Nrf2 and enhanced its stability by preventing its degradation through Keap1-mediated ubiquitination. As expected, fisetin alleviated Aβ-induced ferroptosis in neuronal cells through activation of the Sirt6/Nrf2 axis. CONCLUSION: Fisetin alleviated Aβ-induced neuronal cell ferroptosis by activating the Sirt6/Nrf2 axis. These results underscore fisetin's therapeutic potential for AD by targeting ferroptosis, providing a new strategy for disease intervention.

doi.org/10.1016/j.jneuroim.2025.578699PubMed 40759059Interventions