The FOX Family: Key Regulators in Aging-Related Pathways

The Forkhead box (FOX) family comprises a group of transcription factors distinguished by a wing-like helix structure in their DNA-binding domain and encompasses 19 subfamilies, including Forkhead Box O (FOXO), Forkhead Box M (FOXM), and Forkhead Box P (FOXP), among others. In recent years, the integral involvement of aging regulation, characterized as a genetically regulated process of progressive functional decline, in aging regulation has been highlighted by accumulating evidence. Specifically, FOXO up-regulates inhibitors p21 and p27, leading to cell cycle arrest, resistance to enhances oxidative stress resistance by activating enzymes such as superoxide dismutase (SOD) and catalase (CAT), promotes genomic stability by activating DNA repair through Growth Arrest and DNA Damage-Inducible 45 (GADD45), and initiates autophagy by targeting Beclin 1 (BECN1) and Unc-51 like autophagy activating kinase 2 (ULK2) under stress conditions when the Phosphoinositide 3-kinase (PI3K) - Protein Kinase B (Akt) axis is inhibited. In contrast, FOXM, specifically for FOXM1, has been shown to promote the cell proliferation by antagonizing the p16-pRb axis and the p53 signaling pathway, enhancing DNA damage repair capacity by modulating factors such as Nijmegen breakage syndrome protein (NBS1), and mitigating oxidative stress by regulating antioxidant enzymes such as SOD. Furthermore, FOXP can induce senescence by activating the p53/p21 axis and generating Reactive Oxygen Species (ROS). These processes mentioned above can regulate cellular senescence. Importantly, dysregulation of FOX members has been implicated in the pathogenesis of major aging-related diseases, including neurodegenerative disorders, cardiovascular diseases, and metabolic disorders. These findings underscore the central role of the FOX family in aging-related pathways, highlight its potential as a therapeutic targets to mitigate aging-associated diseases.