Ferroptosis: underlying mechanisms and involvement in neurodegenerative diseases

Yi Wang, HongJing Li, QianXiong He, Rong Zou, JinRui Cai, Lin Zhang

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.