Iron dysregulation: implications for pathology in multiple sclerosis

Abstract In neurological diseases including Alzheimer’s disease, Parkinson’s disease and multiple sclerosis, iron overload is a major contributor to oxidative stress and localized injury. Iron can also cause harm through oxidative stress-independent mechanisms such as protein aggregation and abnormal sphingolipid metabolism. Dysregulation of iron homeostasis may occur systemically or within specific tissues, leading to deficiency, overload or intracellular mislocalization. These alterations disrupt cellular functions and contribute to disease pathology. Iron’s ability to accept and donate electrons is essential for oxygen transport, energy production and DNA synthesis, yet this same reactivity also renders it potentially toxic, as excess iron promotes cellular damage including ferroptosis. Despite extensive research into the functions of iron under physiological conditions and its toxicity when dysregulated, critical questions remain unanswered. Why is iron homeostasis disrupted in the brain? What are the underlying mechanisms driving this dysregulation, and how can the resulting damage be mitigated or reversed? These questions are especially pertinent in the context of demyelinating and neurodegenerative disorders, where iron accumulation is a common pathological feature. In this review, we provide a comprehensive overview of iron biology, emphasizing its chemical properties, cellular functions, and the tightly regulated mechanisms that maintain iron homeostasis. We then discuss the pathological consequences of iron dysregulation in multiple sclerosis and the therapeutic strategies that have been developed to target iron toxicity. While the disease of prominence for this review is multiple sclerosis, we refer to countering iron in Alzheimer’s and Parkinson’s disease to highlight the approaches undertaken to ameliorate iron neurotoxicity.