Targeting GPX4 in neurodegenerative disorder: Unlocking ferroptosis as a therapeutic frontier

Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation and disruption of cellular redox homeostasis. Among the key regulators of this process, glutathione peroxidase 4 (GPX4) plays a central role in maintaining membrane lipid integrity by reducing phospholipid hydroperoxides using glutathione as a cofactor. Impairment of GPX4 activity leads to the accumulation of toxic lipid peroxides, ultimately triggering ferroptotic cell death. Increasing evidence suggests that dysregulation of GPX4-mediated antioxidant defense contributes to the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions characterized by oxidative stress and iron imbalance. In recent years, targeting GPX4 and its associated metabolic pathways has emerged as a promising therapeutic strategy for modulating ferroptosis. This review summarizes the molecular mechanisms governing GPX4 regulation, including its interaction with glutathione metabolism, lipid peroxidation pathways, and iron homeostasis. Furthermore, we discuss emerging pharmacological modulators of GPX4 and ferroptosis, highlighting their potential applications in the treatment of neurological diseases. Understanding the regulatory network surrounding GPX4 may provide new insights into ferroptosis-based therapeutic interventions and facilitate the development of targeted strategies for the management of neurodegenerative disorders.