Iron homeostasis imbalance and ferroptosis in brain diseases

Abstract

Brain iron homeostasis is maintained through the normal function of blood–brain barrier and iron regulation at the systemic and cellular levels, which is fundamental to normal brain function. Excess iron can catalyze the generation of free radicals through Fenton reactions due to its dual redox state, thus causing oxidative stress. Numerous evidence has indicated brain diseases, especially stroke and neurodegenerative diseases, are closely related to the mechanism of iron homeostasis imbalance in the brain. For one thing, brain diseases promote brain iron accumulation. For another, iron accumulation amplifies damage to the nervous system and exacerbates patients’ outcomes. In addition, iron accumulation triggers ferroptosis, a newly discovered iron‐dependent type of programmed cell death, which is closely related to neurodegeneration and has received wide attention in recent years. In this context, we outline the mechanism of a normal brain iron metabolism and focus on the current mechanism of the iron homeostasis imbalance in stroke, Alzheimer's disease, and Parkinson's disease. Meanwhile, we also discuss the mechanism of ferroptosis and simultaneously enumerate the newly discovered drugs for iron chelators and ferroptosis inhibitors.

Antioxidant Systems as Modulators of Ferroptosis: Focus on Transcription Factors

“…The abnormal metabolism of lipids, of which the brain is especially rich, leads to ferroptosis, which can greatly contribute to acute damage to the central nervous system. Indeed, dysregulation of iron homeostasis and excessive ROS in the brain are common hallmarks of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD) [ 84 ]. When neurons die, their iron-containing inclusions are released.…”

Ferroptosis: a new antidepressant pharmacological mechanism

“…The use of etomidate upregulates the expression of BDNF, Nrf2 and GPX4, thereby inhibiting ferroptosis in hippocampal neurons and improving depression-like states in rats. To further investigate the role of ferroptosis in ECT, the researchers administered ferrostatin-1 (Fer-1), as the most potential ferroptosis inhibitor ( LONG et al, 2023 ), to the rats. Western blot analysis indicated significant upregulation of SLC7A11 and GPX4 in the CUMS model rats injected with Fer-1, while the levels of free Fe 2+ decreased.…”

Melatonin MT1 receptors regulate the Sirt1/Nrf2/Ho‐1/Gpx4 pathway to prevent α‐synuclein‐induced ferroptosis in Parkinson's disease

“…3 Iron accumulation and lipid peroxidation have been observed in PD brains, especially in the SN, suggesting a possible link between iron-mediated cell death and PD progression. 4 However, whether and how ferroptosis is involved in PD remains unclear. In this study, we explored the role and mechanism of this irondependent cell death process in PD.…”

“…Iron is vital for cellular functions but can also cause oxidative damage to biomolecules through the Fenton reaction when in excess 3 . Iron accumulation and lipid peroxidation have been observed in PD brains, especially in the SN, suggesting a possible link between iron‐mediated cell death and PD progression 4 . However, whether and how ferroptosis is involved in PD remains unclear.…”