Salidroside alleviates Aβ1–42-induced ferroptosis in human neuroblastoma cells by AKT/GSK-3β activation via inhibiting VDAC1

• Salidroside reduces Aβ1-42-induced ferroptosis in SH-SY5Y cells. • VDAC1 mediates Aβ1-42-induced ferroptosis in SH-SY5Y cells. • Salidroside suppresses ferroptosis via VDAC1 inhibition in SH-SY5Y cells. • VDAC1 modulates ferroptosis through AKT/GSK-3β in SH-SY5Y cells. • Salidroside inhibits VDAC1 and activates AKT/GSK-3β to mitigate ferroptosis. Alzheimer's disease (AD) is a degenerative neurological disease, and SH-SY5Y cells play an important role in the pathogenesis of AD. Salidroside is the main active ingredient of Rhodiola rosea L. The aim of this study was to investigate the effect of salidroside on the induction of ferroptosis in SH-SY5Y cells by Aβ 1-42 . Aβ 1-42 -induced SH-SY5Y cells were used to construct an AD cell model, and cell viability was measured by CCK-8. The expression of ferroptosis-related proteins, VDAC1, and AKT/GSK-3β signaling pathway-related proteins was detected by western blotting; the Fe²⁺ content of cells was determined by an iron content assay kit; the level of ROS in cells was detected by immunofluorescence; and apoptosis was detected by flow cytometry. This research showed that salidroside alleviated Aβ 1-42 -induced ferroptosis in SH-SY5Y cells at an optimal concentration of 30 mM. The expression of GPX4 and FTH1 increased, and the expression of IREB2 decreased after salidroside treatment. The apoptosis rate decreased, as did the intracellular Fe²⁺ content and the level of ROS. After transfection with si-VDAC1, the trend of change was similar to that after salidroside treatment. Furthermore, treatment with an AKT inhibitor and AKT activator demonstrated the involvement of the AKT/GSK-3β signaling pathway in the induction of ferroptosis in SH-SY5Y cells by Aβ 1-42 . The findings suggest that salidroside alleviates cellular ferroptosis by AKT/GSK-3β pathway activation via inhibiting VDAC1.