An Update on Role of Ionizing Radiation to Enhance Proliferation and Differentiation of Normal Stem Cells via Activation of NRF2 Pathway: Review

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.

Keywords: NRF2; PI3K/Ak; differentiation; ionizing radiation; neurogenesis; osteogenesis.

Figure 1

Degradation and activation of the NRF2 pathway under unstressed (A) and oxidative (B) conditions. NRF2 is released from KEAP1 and moves into the nucleus, where it stimulates the production of genes that code for antioxidant enzymes and other proteins. This system is crucial for redox equilibrium maintenance and cell defense against oxidative damage.

Figure 2

Osteogenesis mechanism via activation of NRF2 by IR (oxidative stress). Runx2, Runt-related transcription factor 2; ALP, alkaline phosphatase; Ca²⁺, Calcium; SOD2, superoxide dismutase 2, mitochondrial.

Figure 3

NRF2 activation induces adipogenesis via activation of key pro-adipogenic factors such as C/EBP-α, C/EBP-β, FASN, SCD1, and PPARγ. Samll MAF, musculoaponeurotic fibrosarcoma; SCD1, Stearoyl-CoA 9-desaturase; PPARγ, Peroxisome proliferator-activated receptor gamma; FASN, Fatty acid synthase; C/EBP, leucine zipper CCAAT-enhancer binding protein.

Figure 4

Proposed mechanism for neuronal differentiation-induced NRF2 signaling as well as P13K/Akt/mTOR signaling. NRF2 protein levels increase along with ARE activation.