Iron dysregulation in the central nervous system: implications for autism spectrum disorder

Abstract

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by deficits in social interaction, impaired communication, and restricted, repetitive behaviors. Its pathophysiology involves a complex interplay of genetic, epigenetic, metabolic, and environmental factors. Among these, iron metabolism has emerged as a critical component due to its essential role in brain maturation. Iron supports oxygen transport, mitochondrial ATP production, neurotransmitter synthesis, DNA replication, myelination, and enzyme regulation processes vital for neurodevelopment. Dysregulation of iron homeostasis, both iron deficiency and iron overload, has been frequently observed in individuals with ASD and may contribute to core neurobehavioral symptoms through mechanisms involving neuroinflammation, oxidative stress, mitochondrial dysfunction, and altered synaptic plasticity. Genetic variants affecting iron-regulatory proteins such as transferrin receptor, ferritin, ferroportin, and ceruloplasmin highlight the link between iron imbalance and ASD. Iron deficiency during critical windows of brain development may impair cognitive and behavioral maturation, whereas excessive iron accumulation may trigger glial activation, lipid peroxidation, and ferroptotic death of neurons. Therapeutic strategies differ across developmental stages: normalizing maternal iron status in pregnancy, correcting early-life deficiencies through supplementation of iron-fortified foods, and applying chelation therapies to prevent iron overload. This review integrates molecular, developmental, and clinical evidence to highlight the role of iron dysregulation in ASD with a focus on iron imbalance at different stages of neurodevelopment. Understanding the key mechanisms of iron dysregulation may grant new opportunities to restore iron homeostasis at specific time windows, supporting healthy neurodevelopment.