The FOXO signaling axis displays conjoined functions in redox homeostasis and stemness.

Previous views of reactive oxygen species (ROS) depicted them as harmful byproducts of metabolism as uncontrolled levels of ROS can lead to DNA damage and cell death. However, recent studies have shed light into the key role of ROS in the self-renewal or differentiation of the stem cell. The interplay between ROS levels, metabolism, and the downstream redox signaling pathways influence stem cell fate. In this review we will define ROS, explain how they are generated, and how ROS signaling can influence transcription factors, first and foremost forkhead box-O transcription factors, that shape not only the cellular redox state, but also stem cell fate. Now that studies have illustrated the importance of redox homeostasis and the role of redox signaling, understanding the mechanisms behind this interplay will further shed light into stem cell biology. [Display omitted] • Stem cells exhibit specialized energy metabolism that maintains a healthy redox state. • Oxidative stress aligns with stemness loss and initiation of differentiation. • Stem cells feature specialized redox sensors that conserve stemness. • FOXO transcription factors serve as stem cell redox sensors. • The outcome of FOXO activation might differ between ASCs and PSCs. [ABSTRACT FROM AUTHOR]