FOXO family and neurodegenerative diseases: Mechanisms of action and therapeutic potential

Neurodegenerative diseases (NDDs) lack effective disease-modifying therapies. The FOXO transcription factors serve as integrative hubs of cellular stress responses, operating through cell-autonomous homeostasis, intercellular coordination, intracellular quality control, and cell fate decisions four hierarchical tiers. This review systematically examines isoform-specific functions: FOXO1 governs metabolic reprogramming and mitochondrial biogenesis; FOXO3 acts as the principal oxidative stress sensor with context-dependent neuroprotective or pro-apoptotic outputs; FOXO4 regulates cellular senescence; and FOXO6 maintains synaptic metabolic support. These functions vary across cell types and disease stages, with post-translational modifications determining functional transitions. FOXO proteins participate in complex interactions with disease-specific pathological proteins, either promoting clearance and repair or exacerbating neurodegeneration depending on stress intensity and chronicity. Therapeutic strategies targeting FOXO remain in preclinical and early clinical stages. Key challenges include disease stage-dependent dosing, cell-type-specific delivery, blood-brain barrier penetration, and metabolic side effects. Future directions emphasize biomarker-guided patient stratification and precision interventions aligned with the spatiotemporal dynamics of FOXO signaling. Unlike prior reviews focusing on single pathways or diseases, this work integrates isoform-specific, stage-dependent, and cell-type-resolved FOXO functions into a unifying hierarchical framework.