FOXO family and neurodegenerative diseases: Mechanisms of action and therapeutic potential.
FOXO transcription factors play diverse roles in neurodegenerative diseases, but effective therapies targeting these pathways are still in early development stages.
Where it sits
this study against the rest of the foxo4-dri (foxo4-d-retro-inverso) corpusSummary and findings
This review examines the roles of FOXO transcription factors in neurodegenerative diseases, highlighting their isoform-specific functions and interactions with pathological proteins. It discusses the challenges of developing therapeutic strategies targeting FOXO, which are still in preclinical and early clinical stages. No specific numeric findings or treatment outcomes are reported.
Abstract
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.
Background
The paper addresses the role of the FOXO family of transcription factors in neurodegenerative diseases, which is an area of growing interest due to the potential for therapeutic targeting. Previous research has indicated that FOXO proteins are involved in cellular stress responses and longevity, but their specific mechanisms in neurodegenerative contexts remain unclear. Understanding these mechanisms could inform the development of new therapeutic strategies.
Methods
Not reported in abstract.
Results
Not reported in abstract.
Interpretation
Not reported in abstract.
Key findings
- Not reported in abstract.
Limitations
- Not reported in abstract.