New Perspectives on oligodendrocytes: Guardians of iron homeostasis and defenders against ferroptosis.

BACKGROUND: 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.

AIM OF REVIEW: 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.

KEY SCIENTIFIC CONCEPTS OF REVIEW: 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.