Fisetin Attenuates Amyloid‐Beta‐Induced Neurotoxicity in Human Neuroblastoma SH‐SY5Y Cells: Integrating In Silico Target Prediction and In Vitro Validation

ABSTRACT

The accumulation of amyloid beta (Aβ) and tau tangles in the brain leads to Alzheimer's disease (AD). Fisetin, a natural flavonoid, is an antioxidant molecule, and its neuroprotective effects are not clearly understood. Therefore, attempts have been made to evaluate the neuroprotective effects of fisetin using in silico methods and an Aβ1‐42‐induced neurotoxicity model in human neuroblastoma SH‐SY5Y cells. In silico studies demonstrated that fisetin binds strongly and with high stability to different proteins, such as ULK1 (autophagy marker), p21 (senescence/cell cycle marker), and synaptophysin (synaptic marker), which are responsible for maintaining brain health and are implicated in AD. Moreover, Aβ1‐42 was also found to bind to these protein targets, indicating that Aβ1‐42 and fisetin both target common binding sites. In vitro studies on SH‐SY5Y cells further confirmed that fisetin promotes cell survival under the toxic effects of Aβ1‐42. It reduced oxidative stress and restored the activities of ion channels, which were impaired by Aβ1‐42 treatment. Fisetin increased antioxidant defense and restored the activity of molecules that control brain signals. Overall, fisetin acts on multiple targets to protect neurons by reducing oxidative damage, supporting ion channel activity, and inducing the autophagy process.