• Summarizes the dual and interconnected roles of oligodendrocytes (OLs) as the principal cellular iron reservoir essential for myelination and as defenders against iron-dependent ferroptosis, framing this balance as central to central nervous system health. • Describes the precise metabolic machinery governing iron homeostasis in the OL lineage, detailing the developmentally regulated functions of key proteins. • Explores the contrasting vulnerability between oligodendrocyte progenitor cells (OPCs) and mature OLs to ferroptosis, linking the high susceptibility of OPCs to their metabolic state, and establishes the resilience of mature OLs as a critical prerequisite for sustained myelination. • Highlights the sophisticated, multi-layered anti-ferroptosis defense system in mature OLs, which integrates reprogrammed iron metabolism with a specialized selenoprotein-based antioxidant hub. • Reviews how the disruption of iron homeostasis and the collapse of anti-ferroptotic defenses in OLs underpin a vicious cycle of demyelination and neurodegeneration in multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD), proposing the iron-myelin axis as a promising therapeutic target. Oligodendrocytes (OLs) play a pivotal role in preserving iron homeostasis within the central nervous system (CNS), as they harbor the largest cellular iron reservoir essential for myelination. However, this indispensable function places OLs at heightened risk of ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation. The susceptibility of OLs to ferroptosis has significant implications for CNS health, particularly in the context of neurodegenerative diseases where OL dysfunction exacerbates demyelination and accelerates disease progression. This review aims to systematically elucidate the mechanisms by which mature OLs balance their dual roles as guardians of iron homeostasis and defenders against ferroptosis. Furthermore, it aims to underscore the ramifications of impaired OL iron regulation in prominent neurodegenerative conditions and to investigate potential therapeutic interventions aimed at bolstering OL resilience. Mature OLs employ a sophisticated, multi-layered defense system to maintain iron homeostasis and prevent ferroptosis, encompassing precise metabolic regulation of iron uptake and storage, alongside a specialized antioxidant network centered on selenoprotein synthesis. Disruption of this delicate balance renders OLs vulnerable in diseases such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD), leading to a vicious cycle of OL death, iron dysregulation, and demyelination. Targeting OL iron homeostasis and anti-ferroptotic pathways through iron modulation, antioxidant reinforcement, or direct ferroptosis inhibition represents a promising strategy to promote remyelination and mitigating neurodegeneration.
Li et al. (Wed,) studied this question.