Exploring ferroptosis: Unraveling its potential role in autistic spectrum disorder

Autism spectrum disorder (ASD) is a diverse neurodevelopmental disorder characterized by ambiguous etiological mechanisms and the absence of recognized disease-modifying pharmacotherapies. Ferroptosis, an iron-dependent and lipid peroxidation-driven mechanism of regulated cell death, has been associated with neurodevelopment and neurodegeneration, prompting interest in its potential role in ASD. This narrative review consolidates from molecular and clinical studies, animal models, and in vitro systems to assess ferroptosis as a candidate mechanistic pathway, biomarker source, and therapeutic target in ASD. Peripheral transcriptomic analyses reveal differentially expressed ferroptosis-related genes, ferroptosis-based molecular clusters, and immune-activated subtype in children with ASD, facilitating the development of ferroptosis-derived diagnostic and scoring models with modest yet reproducible discrimination. Clinical data associate maladaptive polyunsaturated fatty acid profiles, increased lipid peroxidation products, and adverse docosahexaenoic acid/arachidonic acid ratio with autistic social impairments, aligning with ferroptosis-prone conditions. In rodent models, genetic or pharmacological modulation of DDIT4-PI3K/Akt signaling, Nrf2/GPX4/xCT antioxidant systems, and ferritinophagy mitigates ASD-like social deficits, repetitive behaviors, anxiety-like phenotypes, and liver pathology. Induced pluripotent stem cell-derived neural progenitors from autistic children with megalencephaly exhibit heightened oxidative and iron stress, alongside active resistance to ferroptosis mediated by upregulated GPX4 and selenoprotein pathways, indicating subtype-specific ferroptosis resistance. These findings suggest a complex, context-dependent role of ferroptosis and ferroptosis resistance in ASD, interacting with immune dysregulation, redox imbalance, and peripheral organ involvement. Nevertheless, longitudinal and interventional studies integrating brain, peripheral, and cellular data are required to establish causality, define meaningful ferroptosis-related signatures, and evaluate the safety and efficacy of ferroptosis-modulating interventions.