Ferroptosis, a Regulated Neuronal Cell Death Type After Intracerebral Hemorrhage

Abstract

Ferroptosis is a term that describes one form of regulated non-apoptotic cell death. It is triggered by the iron-dependent accumulation of lipid peroxides. Emerging evidence suggests a link between ferroptosis and the pathophysiological processes of neurological disorders, including stroke, degenerative diseases, neurotrauma, and cancer. Hemorrhagic stroke, also known as intracerebral hemorrhage (ICH), belongs to a devastating illness for its high level in morbidity and mortality. Currently, there are few established treatments and limited knowledge about the mechanisms of post-ICH neuronal death. The secondary brain damage after ICH is mainly attributed to oxidative stress and hemoglobin lysate, including iron, which leads to irreversible damage to neurons. Therefore, ferroptosis is becoming a common trend in research of neuronal death after ICH. Accumulative data suggest that the inhibition of ferroptosis may effectively prevent neuronal ferroptosis, thereby reducing secondary brain damage after ICH in animal models. Ferroptosis has a close relationship with oxidative damage and iron metabolism. This review reveals the pathological pathways and regulation mechanism of ferroptosis following ICH and then offers potential intervention strategies to mitigate neuron death and dysfunction after ICH.

Keywords: antioxidation; ferroptosis; intracerebral hemorrhage; iron metabolism; lipid peroxidation.

Figure 1

The lipid peroxidation pathway and the antioxidant system of ferroptosis. System xc⁻ exports glutamate out of the cell and imports cystine into the cell. Cystine in the cell is reduced to cysteine, which combined with glycine and glutamate for the synthesis of GSH. GSH is a synthetic substrate for glutathione peroxidase 4 (GPX4), which can resist lipid peroxidation and ferroptosis. FSP1 is transferred to the plasma membrane through myristoylation, where it mediates the reduction of CoQ10 to ubiquinol using NAD(P)H, which inhibits lipid peroxides. Vitamin E can inhibit lipid peroxidation with its radical-trapping activities. GSH, glutathione; FSP1, ferroptosis suppressor protein 1; CoQ10, coenzyme Q10; NAD(P)H, nicotinamide adenine dinucleotide phosphate.

Figure 2

The iron metabolism-related pathway in ferroptosis. In the plasma, Fe(III) combined with TF to form TBI, which bound to TfR1 internalized by endocytosis. Iron is liberated from TF and reduced to Fe(II) in the endosome, which was transported into the cytosol by ZIP14/8 and divalent metal transporter 1 (DMT1) interacted by PCBP2. NCOA4 can directly deliver ferritin to the autophagosome, and it is degraded to Fe(III) for heme synthesis. Heme is degraded to Fe(II) by HO-1, which is transported out of the cell by Fpn. The expression of HO-1 can be upregulated by oxidative stress through the p62-Keap1-NRF2 pathway, thereby inducing ferroptosis. TF, transferrin; TBI, transferrin-bound iron; TfR, transferrin receptor; ZIP, ZRT/IRT-like protein; DM, divalent metal transporter; PCBP, poly rC binding protein; NCOA4, nuclear co-activator 4; Poly rC, binding protein; HO-1, heme oxygenase.

Figure 3

The regulatory mechanism of ferroptosis following intracerebral hemorrhage (ICH). After ICH, the heme incorporates into the plasma membrane and enhances lipid peroxidation by increasing the sensitivity to exogenous H₂O₂. N-acetylcysteinean can decrease toxic lipids produced by ALOX5 and increase the level of cysteine to prevent lipid peroxidation. Selenium, delivered into the brain, could increase the level of GPX4. Fe(II) through both Fpn1 input and DMT1 output increases after ICH. ALOX5, arachidonate-dependent arachidonate 5-lipoxygenase.

Figure 4

Changes of ferroptosis regulators after ICH. After ICH, Hb/heme/iron plays an indispensable role in the production of reactive oxygen species (ROS). The expression of GSH and GPX4 was reduced. DMT1, Fpn, ferritin, TF, TfR, and HO-1 levels were increased.