Betaine alleviates neuronal impairment in glutamate-injured SH-SY5Y neuroblastoma cells via Nrf2 signaling pathway related ferroptosis

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that currently lacks efficacious therapeutic interventions. It's well documented that ferroptosis is extensively involved in the progression and pathogenesis of AD. Betaine, a critical nutrient for mammal health, is reported to possess neuroprotective actions. The objective of the current research was to investigate whether betaine could mitigate neuronal impairments by suppressing ferroptosis in SH-SY5Y neuroblastoma cells injured by glutamate. The results indicate that betaine improved the survival rate and reversed morphology changes of glutamate-damaged SH-SY5Y cells. Additionally, betaine reduced the intracellular accumulation of Fe 2+ , malondialdehyde (MDA), lipid reactive oxygen species (ROS), and lactate dehydrogenase (LDH) release induced by glutamate. And reversed the decreased glutathione (GSH) content and downregulation of ferroptosis inhibitor glutathione peroxidase 4 (GPX4) expression were observed upon betaine administration. Additionally, betaine facilitated the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) from the cytoplasm to the nucleus in SH-SY5Y cells induced by glutamate. Molecular docking validated high-affinity binding between betaine and Nrf2. Collectively, betaine could exert neuroprotective effects by alleviating ferroptosis via activation of the Nrf2 pathway, thereby positioning it as a potential candidate for targeting ferroptosis-driven neurodegeneration in AD.