Emerging Mechanisms and Targeted Therapy of Ferroptosis in Neurological Diseases and Neuro-oncology

Abstract

Ferroptosis is a novel type of cell death characterized by iron-dependent lipid peroxidation that involves a variety of biological processes, such as iron metabolism, lipid metabolism, and oxidative stress. A growing body of research suggests that ferroptosis is associated with cancer and neurodegenerative diseases, such as glioblastoma, Alzheimer's disease, Parkinson's disease, and stroke. Building on these findings, we can selectively induce ferroptosis for the treatment of certain cancers, or we can treat neurodegenerative diseases by inhibiting ferroptosis. This review summarizes the relevant advances in ferroptosis, the regulatory mechanisms of ferroptosis, the participation of ferroptosis in brain tumors and neurodegenerative diseases, and the corresponding drug therapies to provide new potential targets for its treatment.

Keywords: GPX4; GSH; ferroptosis; iron metabolism; lipid peroxidation; neurodegenerative diseases.

Figure 1

An overview of ferroptosis and associated neurological diseases. The treatment of neuroblastoma and meningioma, can be improved by exploiting the effects of ferroptosis. Treatment with Fer-1 can significantly reduce the levels of ROS, IL-1β, TNFα and other inflammatory factors. Ferroportin1 is likely downregulated in the brain tissues of AD patients. The main pathological feature of AD is the deposition of amyloid beta peptide in the brain leading to the death of nerve cells. FTH1 may provide a key link between ferroptosis and ferritinophagy in disease and regulating FTH1 may be therapeutically beneficial in the pathophysiology of PD. Ferroptosis inhibitors can alleviate lipid peroxidation and cell death caused by heme toxicity, and hemorrhagic stroke will show molecular features of ferroptosis.

Figure 2

Signaling pathways of ferroptosis and associated neurological diseases. Ferroptosis is a cancer therapy, which mainly induces cancer cell death by promoting the fenton reaction to accelerate the production of ROS. ACSL4 inhibits the increase of glioma cells by activating ferroptosis. Chemical ferroptosis inhibitors, such as Fer-1, deferoxamine, and the vitamin E analog Trolox, reduce ICH-induced cytotoxicity when treated in vitro. Brain cells in patients with AD have been observed to exhibit biochemical and morphological features similar to ferroptosis, including GSH degradation, GPX4 inactivation, increased ROS due to iron metabolism imbalance, lipid peroxidation, and mitochondrial abnormalities. Ferrostatin-1 derivatives and PKC inhibitors can also alleviate the progression of ferroptosis in PD. Inflammation, excitatory toxicity, iron accumulation and oxidative stress occur during the onset of stroke. The use of iron chelating agents, antioxidants, and free radical scavengers can reduce cerebrovascular damage after stroke.

Figure 3

Targeting ferroptosis strategies (including clinical medications and experimental compounds). Ferroptosis agonists: The first class includes drugs such as Erastin, sulfasalazine, and sorafenib, among which sorafenib is effectively used in the treatment of liver cancer, and its effect can be inhibited by ferroptosis inhibitors. The second class of drugs directly inhibits or combines GPX4 to induce ferroptosis, and related drugs include the ferroptosis inducers FIN56 and RSL3. The third category includes drugs that reduce intracellular GSH levels, such as cisplatin, which have been used for the treatment of ovarian cancer, lung cancer, thyroid cancer, lymphosarcoma and other cancers. Although other iron chelating agents have also shown blocking effects on ferroptosis in vitro experiments or animal models, only DFP has currently entered clinical trials, which may be related to the fact that DFP can cross the blood-brain barrier. Ferroptosis inhibitors exert an anti-inflammatory effect by inhibiting the expression of inflammatory factors in spinal cord contusion (SCI), including IL-1β, TNFα, and ICAM-1.