Ferroptosis-A Novel Mechanism With Multifaceted Actions on Stroke

Abstract

As a neurological disease with high morbidity, disability, and mortality, the pathological mechanism underlying stroke involves complex processes such as neuroinflammation, oxidative stress, apoptosis, autophagy, and excitotoxicity; but the related research on these molecular mechanisms has not been effectively applied in clinical practice. As a form of iron-dependent regulated cell death, ferroptosis was first discovered in the pathological process of cancer, but recent studies have shown that ferroptosis is closely related to the onset and development of stroke. Therefore, a deeper understanding of the relationship between ferroptosis and stroke may lead to more effective treatment strategies. Herein, we reviewed the mechanism(s) underlying the onset of ferroptosis in stroke, the potential role of ferroptosis in stroke, and the crosstalk between ferroptosis and other pathological mechanisms. This will further deepen our understanding of ferroptosis and provide new approaches to the treatment of stroke.

Keywords: amino acid metabolism; apoptosis; autophagy; ferroptosis; inflammation; iron overload; lipid peroxidation; stroke.

Figure 1

Mechanism governing ferroptosis in stroke. With respect to iron metabolism, after ischemic or hemorrhagic stroke, the permeability of the blood-brain barrier (BBB) increases, causing a variety of components rich in Fe³⁺ in the bloodstream to infiltrate into the brain parenchyma. Fe³⁺ binds closely to transferrin (T) to form iron-containing TF, which then binds to TFR1 on the surface of brain cell membranes, enters cells through pinocytosis, and forms an endosome. In the acidic environment of an inclusion body, Fe³⁺ is released from TF, catalyzed by ferrous reductase to Fe²⁺, and transported to the cytoplasm through the corresponding transporter. Fe²⁺ then initiates the Fenton reaction to form reactive oxygen species (ROS) and also affects the catalytic activity of lipoxygenase (LOX). In addition, the Fe²⁺ in the cytoplasm can be absorbed by PCBP1 and iron is loaded on the iron-free form of HIF-PDH1. Iron-containing HIF-PDH1 together with other stimuli drives the activity of pro-ferroptosis ATF4 gene expression. With regard to amino acid metabolism, a high concentration of extracellular glutamate leads to a dysfunction in system XC⁻, a deficiency in intracellular cystine, depletion of GSH, and diminution in GPX4 activity. In addition, glutamate binds to its receptor (NMDAR), and the activation of NMDAR then further exacerbates iron uptake. Regarding lipid metabolism, as the main component of phospholipid membranes, arachidonic acid (AA) is esterified with phosphatidylethanolamine (PE) under the action of ACSL4 and LPCAT3 to synthesize PE-AA and is then catalyzed by LOX to PE-AA-OH. As shown in the figure, these three components together lead to lipid peroxidation and ferroptosis.

Figure 2

Crosstalk between ferroptosis and other pathological processes in stroke. As shown in the figure, the pathological stimulation caused by stroke causes ferroptosis in damaged neurons; and as one of the core events in cell injury, ferroptosis can then further promote neuroinflammation, autophagy, and apoptosis. Ferroptosis is triggered interactively with these pathological processes and participates in a close one-way or even two-way relationship so that, in the process of stroke, these key constituents initiate a variety of cascade reactions and jointly determine the survival of neurons.