Insights into the Role of the PI3K/AKT Pathway in Regulating Ferroptosis in Central Nervous System Diseases

Abstract

Ferroptosis is a form of iron-dependent cell death that differs from apoptosis. Key characteristics of cells undergoing ferroptosis include iron overload, lipid peroxidation, glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) expression inhibition, and cystine/glutamate antiporter system Xc- damage. Ferroptosis is common in nervous system diseases. The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT) is a classic intracellular signal transduction pathway that responds to extracellular signals and promotes proliferation, growth, metabolism, and angiogenesis. The imbalance of the PI3K/AKT signaling pathway might lead to a series of diseases. Although there have been many studies on the role of this signaling pathway in central nervous system (CNS) diseases, the impact of this axis on mediating ferroptosis in CNS diseases has not been summarized. In this review, we will elucidate the role of PI3K/AKT in mediating ferroptosis in several main CNS diseases, including ischemic stroke (IS), intracranial cerebral hemorrhage (ICH), Alzheimers disease (AD), Parkinsons disease (PD), and glioblastoma (GBM), to provide valuable insights for both clinical endeavors and scientific investigations in the future.