FOXO3 involvement in neurological OxInflammation

Graphical abstract Abstract The interplay between oxidative stress and inflammation, often referred to as OxInflammation, represents a central pathological mechanism in many neurological disorders. Within the central nervous system, this interplay involves a feedforward loop between redox imbalance and innate immune activation, forms a self-perpetuating cycle that disrupts mitochondrial homeostasis, amplifies glial reactivity, and exacerbates neuronal damage. Among redox-sensitive regulators, forkhead box O (FOXO) transcription factors have emerged as key modulators of cellular adaptation to oxidative and inflammatory stress. FOXOs integrate metabolic growth factors and stress-activated signaling pathways to promote transcriptional programs controlling antioxidant defense, autophagy, apoptosis, and immune responses depending on the context and on the activators. FOXO3a activity is tightly controlled by post-translational modifications and cofactor interactions, which determine its nuclear–cytoplasmic localization and target gene selectivity. Over time, this OxInflammatory milieu leads to progressive neuroinflammation, synaptic dysfunction, neuronal death, and impaired repair mechanisms, underlying the pathogenesis of neurodegenerative disorders, such as Alzheimer’s disease (AD), multiple sclerosis (MS), autism spectrum disorder (ASD), and Rett syndrome (RTT). Increasing evidence implicates aberrant FOXO3a regulation in both neurodegenerative and neurodevelopmental disorders, positioning it as a molecular nexus linking oxidative stress to inflammatory pathology. This review highlights how FOXO3a serves as a central switch in redox and inflammatory signaling during neurological diseases and highlights its therapeutic potential as a molecular target to restore homeostasis in oxidative–inflammatory states, particularly in AD, MS, ASD, and RTT.