The Latest Articles on Ferroptosis and Neurodegenerative Diseases
Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.
This week, we would like to share several latest articles on Ferroptosis and Neurodegenerative Diseases.
Title: Molecular mechanisms of ferroptosis and their involvement in brain diseases
Authors: Inês Costa, Daniel José Barbosa, Sofia Benfeito, Vera Silva, Daniel Chavarria, Daniel Chavarria, Fernando Remião, Fernando Remião
Type: Review
Abstract:
Ferroptosis is a type of regulated cell death characterized by intracellular accumulation of iron and reactive oxygen species, inhibition of system Xc-, glutathione depletion, nicotinamide adenine dinucleotide phosphate oxidation and lipid peroxidation. Since its discovery and characterization in 2012, many efforts have been made to reveal the underlying mechanisms, modulating compounds, and its involvement in disease pathways.
Ferroptosis inducers include erastin, sorafenib, sulfasalazine and glutamate, which, by inhibiting system Xc-, prevent the import of cysteine into the cells. RSL3, statins, Ml162 and Ml210 induce ferroptosis by inhibiting glutathione peroxidase 4 (GPX4), which is responsible for preventing the formation of lipid peroxides, and FIN56 and withaferin trigger GPX4 degradation.
On the other side, ferroptosis inhibitors include ferrostatin-1, liproxstatin-1, α-tocopherol, zileuton, FSP1, CoQ10 and BH4, which interrupt the lipid peroxidation cascade. Additionally, deferoxamine, deferiprone and N-acetylcysteine, by targeting other cellular pathways, have also been classified as ferroptosis inhibitors.
Increased evidence has established the involvement of ferroptosis in distinct brain diseases, including Alzheimer's, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, multiple sclerosis, and Friedreich's ataxia. Thus, a deep understanding of how ferroptosis contributes to these diseases, and how it can be modulated, can open a new window of opportunities for novel therapeutic strategies and targets. Other studies have shown a sensitivity of cancer cells with mutated RAS to ferroptosis induction and that chemotherapeutic agents and ferroptosis inducers synergize in tumor treatment. Thus, it is tempting to consider that ferroptosis may arise as a target mechanistic pathway for the treatment of brain tumors.
Therefore, this work provides an up-to-date review on the molecular and cellular mechanisms of ferroptosis and their involvement in brain diseases. In addition, information on the main ferroptosis inducers and inhibitors and their molecular targets is also provided.
Access this article: https://doi.org/10.1016/j.pharmthera.2023.108373
Title: Inhibition of ferroptosis through regulating neuronal calcium homeostasis: An emerging therapeutic target for Alzheimer's disease
Authors: Yiran Sun, Chenchen Yan, Libo He, Shixie Xiang, Pan Wang, Zhonghua Li, Yuanzhao Chen, Jie Zhao, Ye Yuan, Wang Wang, Xiaowei Zhang, Pan Su, Yunfang Su, Jinlian Ma, Jiangyan Xu, Quekun Peng, Huifen Ma, Zhishen Xie, Zhenqiang Zhang
Type: Review
Abstract:
Alzheimer's disease (AD), a chronic and progressive neurodegenerative disease, generates a serious threat to the health of the elderly. The AD brain is microscopically characterized by amyloid plaques and neurofibrillary tangles. There are still no effective therapeutic drugs to restrain the progression of AD though much attention has been paid to exploit AD treatments. Ferroptosis, a type of programmed cell death, has been reported to promote the pathological occurrence and development of AD, and inhibition of neuronal ferroptosis can effectively improve the cognitive impairment of AD. Studies have shown that calcium (Ca2+) dyshomeostasis is closely related to the pathology of AD, and can drive the occurrence of ferroptosis through several pathways, such as interacting with iron, and regulating the crosstalk between endoplasmic reticulum (ER) and mitochondria. This paper mainly reviews the roles of ferroptosis and Ca2+ in the pathology of AD, and highlights that restraining ferroptosis through maintaining the homeostasis of Ca2+ may be an innovative target for the treatment of AD.
Access this article: https://doi.org/10.1016/j.arr.2023.101899
Title: Ferroptosis-related metabolic mechanism and nanoparticulate anticancer drug delivery systems based on ferroptosis
Authors: Danni Yan, Zhenghong Wu, Xiaole Qi
Type: Review
Abstract:
Ferroptosis is a new type of cell death discovered in recent years that distinguishes from apoptosis and necrosis, mainly caused by the imbalance between the production and degradation of lipid reactive oxygen species in cells. Although the mechanism of ferroptosis is not yet clear, the phenomenon of ferroptosis has attracted widespread attention from researchers and has become a new hotspot in anti-tumor research. Studies have shown that ferroptosis is involved in the occurrence and development of a variety of diseases such as nervous system diseases, cardiovascular diseases and cancer. And inhibiting or inducing the occurrence of ferroptosis can effectively intervene in related diseases. At the same time, nanotechnology, by virtue of its distinct advantages, has been widely used in the development of nanodrug delivery systems. This review outlines current the advance on the intersection of ferroptosis and biomedical nanotechnology. In this review, the discovery and characteristics of ferroptosis, the mechanism of occurrence and the relationship with disease are summarized. More importantly, we summarized the strategies for inducing ferroptosis based on nanoparticulate drug delivery systems for cancer treatment.
Access this article: https://doi.org/10.1016/j.jsps.2023.02.008
Title: Loureirin C inhibits ferroptosis after cerebral ischemia reperfusion through regulation of the Nrf2 pathway in mice
Authors: Yeshu Liu, Yan Mi, Yongping Wang, Qingqi Meng, Libin Xu, Yueyang Liu, Di Zhou, Yingjie Wang, Dong Liang, Wei Li, Ning Li, Yue Hou
Type: Research Article
Abstract:
Background
Ischemic stroke (IS) is considered as a serious cerebral vascular disease. Ferroptosis is a novel type of regulated cell death (RCD), that closely related to the occurrence and progress of IS. Loureirin C, a type of dihydrochalcone compound derived from the Chinese Dragon's blood (CDB). The effective components extracted from CDB have shown neuroprotective effects in ischemia reperfusion models. However, the role of Loureirin C in mice after IS is not well understood. Thus, it is worth to identify the effect and mechanism of Loureirin C on IS.
Purpose
The present research aims to prove the existence of ferroptosis in IS and explore whether Loureirin C can inhibit ferroptosis by regulating nuclear factor E2 related factor 2 (Nrf2) pathway in mice and exert neuroprotective effects on IS models.
Methods
Middle cerebral artery occlusion and reperfusion (MCAO/R) model was established to evaluate the occurrence of ferroptosis and the potential Loureirin C brain-protective effect in vivo. The analysis of free iron, glutamate content, reactive oxygen species (ROS) and lipid peroxidation levels, along with transmission electron microscope (TEM) was applied to prove the existence of ferroptosis. The function of Loureirin C on Nrf2 nuclear translocation was verified by immunofluorescence staining. In vitro, primary neurons and SH-SY5Y cells were processed with Loureirin C after oxygen and glucose deprivation-reperfusion (OGD/R). ELISA kits, western blotting, co-immunoprecipitation (Co-IP) analysis, immunofluorescence, and quantitative real-time PCR were devoted to proving the neuroprotective effects of Loureirin C on IS via regulating ferroptosis and Nrf2 pathways.
Results
The results showed that Loureirin C not only dramatically alleviated brain injury and inhibited neurons ferroptosis in mice after MCAO/R, but also dose-dependently reduce ROS accumulation in ferroptosis after OGD/R. Further, Loureirin C inhibits ferroptosis by activating Nrf2 pathway, and promoting nuclear translocation of Nrf2. Besides, Loureirin C increases heme oxygenase 1 (HO-1), quinone oxidoreductase 1 (NQO1) and glutathione peroxidase 4 (GPX4) content after IS. Intriguingly, the anti-ferroptosis effect of Loureirin C is weakened by Nrf2 knockdown.
Conclusion
Our discoveries first revealed that the inhibitory action of Loureirin C on ferroptosis may greatly depend on its adjusting effect on the Nrf2 pathway, suggesting that Loureirin C could act as a novel anti-ferroptosis candidate and play a therapeutic role in IS. These novel discoveries on the role of Loureirin C on IS models reveal an innovative method that may contribute to neuroprotection for the prevention of IS.
Access this article: https://doi.org/10.1016/j.phymed.2023.154729
Title: Mitoglitazone ameliorates renal ischemia/reperfusion injury by inhibiting ferroptosis via targeting mitoNEET
Authors: Yuanbo Qi, Mingyao Hu, Yang Qiu, Yang Qiu, Luyu Zhang, Luyu Zhang, Yi Feng, Chenghao Feng, Xinyue Hou, Zhigang Wang, Di Zhang, Jie Zhao
Type: Research Article
Abstract:
Ischemia/reperfusion- (I/R-) induced injury is unavoidable and a major risk factor for graft failure and acute rejection following kidney transplantation. However, few effective interventions are available to improve the outcome due to the complicated mechanisms and lack of appropriate therapeutic targets. Hence, this research aimed to explore the effect of the thiazolidinedione (TZD) compounds on I/R-induced kidney damage. One of the main causes of renal I/R injury is the ferroptosis of renal tubular cells. In this study, compared with the antidiabetic TZD pioglitazone (PGZ), we found its derivative mitoglitazone (MGZ) exerted significantly inhibitory effects on erastin-induced ferroptosis by suppressing mitochondrial membrane potential hyperpolarization and lipid ROS production in HEK293 cells. Moreover, MGZ pretreatment remarkably alleviated I/R-induced renal damages by inhibiting cell death and inflammation, upregulating the expression of glutathione peroxidase 4 (GPX4), and reducing iron-related lipid peroxidation in C57BL/6 N mice. Additionally, MGZ exhibited excellent protection against I/R-induced mitochondrial dysfunction by restoring ATP production, mitochondrial DNA copy numbers, and mitochondrial morphology in kidney tissues. Mechanistically, molecular docking and surface plasmon resonance experiments demonstrated that MGZ exhibited a high binding affinity with the mitochondrial outer membrane protein mitoNEET. Collectively, our findings indicated the renal protective effect of MGZ was closely linked to regulating the mitoNEET-mediated ferroptosis pathway, thus offering potential therapeutic strategies for ameliorating I/R injuries.
Access this article: https://doi.org/10.1016/j.taap.2023.116440
