Abstract
Ionizing radiation (IR) as a stress inducer has a significant impact on various normal
stem cells differentiation through activation of various signaling pathways. Low levels of
oxidative stress of IR may preserve or even enhance cell differentiation. In response to IR,
reactive oxygen species (ROS) can activate various signaling pathways that promote cell
differentiation, notably through the involvement of nuclear factor erythroid 2–related factor
2 (NRF2). NRF2 interacts with multiple pathways, including Wnt/β-catenin (osteogenesis),
PPARγ (adipogenesis), and BDNF/TrkB (neurogenesis). This response is dose-dependent:
low doses of IR activate NRF2 and support differentiation, while high doses can overwhelm
the antioxidant system, resulting in cell death. However, the quality of various types of
IR, such as proton and carbon ion radiation, may have a varied impact on stem cells (SCs)
differentiation compared to X-rays. Hence, activation of the NRF2 signaling pathway in
SCs and cell differentiation depends on the level of stress and the quality and quantity
of IR. This review is an update to explore how IR modulates SCs fate toward osteogenic,
adipogenic, and neurogenic lineages through the NRF2 signaling pathway. We highlight
mechanistic insights, dose-dependent effects, and therapeutic implications, bridging gaps
between experimental models and clinical translation.