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Ferroptosis: underlying mechanisms and involvement in neurodegenerative diseases

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Abstract

Ferroptosis, a mode of cell death that was recently identified in 2012, is driven by iron-dependent lipid peroxidation and distinct from other mechanisms of cell death such as autophagy and apoptosis. Ferroptosis has the unique features of disruptions in iron equilibrium, iron-induced lipid peroxidation, and the accumulation of glutamate-induced cellular toxicity. The regulation of ferroptosis mainly involves the iron, lipid, and amino acid metabolic pathways, which are controlled by system Xc−, voltage-dependent anion channels, p53 and other pathways. Neurodegenerative diseases involve gradual neuronal loss predominantly within the central nervous system and are categorized into both sporadic and rare hereditary disorders. These diseases result in the progressive decline of specific neuron populations and their interconnections. Recent investigations have revealed a strong correlation between the manifestation and progression of neurodegenerative diseases and ferroptosis. The pharmacological modulation of ferroptosis, whether by induction or inhibition, exhibits promising prospects for therapeutic interventions for these diseases. This review aims to examine the literature on ferroptosis and its implications in various neurodegenerative diseases. We hope to offer novel insights into the potential therapies targeting ferroptosis in central nervous system neurodegenerative diseases. However, there are still limitations of this review. First, despite our efforts to maintain objectivity during our analysis, this review does not cover all the studies on ferroptosis and neurodegenerative diseases. Second, cell death in neurodegenerative diseases is not solely caused by ferroptosis. Future research should focus on the interplay of different cell death mechanisms to better elucidate the specific disease pathogenesis.

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Acknowledgements

We thank Professor. XianJun Zhu from Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China for providing long-term support in scientific research and constructive suggestions in this review.

Funding

This work was supported by The National Natural Science Foundation of China (82071009), the Department of Science and Technology of Qinghai Province (2022-HZ-814), program from the Department of Science and Technology of Sichuan Province (2023YFS0038).

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  1. Yi Wang and HongJing Li contributed equally to this work.

Authors and Affiliations

  1. The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China

    Yi Wang, HongJing Li, Rong Zou, JinRui Cai & Lin Zhang

  2. Department of Ophthalmology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China

    QianXiong He

  3. Key Laboratory of Tibetan Medicine Research, Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Chinese Academy of Sciences, Northwest Institute of Plateau Biology, Xining, 810008, Qinghai, China

    Lin Zhang

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L.Z. designed and supervised the study. Y.W. and HJ.L. performed literature searching and wrote the majority of the manuscript. QX.H., R.Z. and JR.C. provided constructive advice on the revision of the draft.

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Correspondence to Lin Zhang.

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Wang, Y., Li, H., He, Q. et al. Ferroptosis: underlying mechanisms and involvement in neurodegenerative diseases. Apoptosis 29, 3–21 (2024). https://doi.org/10.1007/s10495-023-01902-9

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