Fig. 3

Context-dependent regulation of FOXOs in stem cell differentiation. FOXO transcription factors play a pivotal role in stem cell differentiation by orchestrating gene expression and cellular processes. However, their impact on differentiation is nuanced and contingent upon specific contexts, with the potential for both promotion and inhibition based on their transcriptional targets. Different members of the FOXO family exhibit distinct roles in stem cell differentiation; for example, FOXO1/3 inhibits neural stem cell (NSC) differentiation into neurons, while FOXO4 promotes neurogenesis of embryonic stem cells (ESCs). FOXO1/4 inhibits myoblast differentiation, whereas FOXO3 promotes the differentiation of satellite cells. During osteogenic differentiation, FOXOs exert stage-specific functions through interactions with various factors, such as RUNX2 in early progenitors, β‐catenin in osteoblast precursors, and ALP, ATF4, and OCN in mature osteoblasts. Both FOXO1 and FOXO3 are essential for mesenchymal stem cells (MSCs) to differentiate into chondrocytes. The role of FOXO1 in adipogenic differentiation is influenced by the specific cell type and cellular context. Furthermore, FOXO1 and FOXO3 are indispensable for the proper development and differentiation of hematopoietic stem cells (HSCs) into their respective lymphoid or myeloid cell lineages