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It has been well established that reactive oxygen species (ROS) play a critical role in ionizing radiation (IR)-induced hematopoietic injury. Theaflavin (TF), a polyphenolic compound from black tea, has been implicated in the regulation of endogenous cellular antioxidant systems. However, it remains unclear whether TF could ameliorate IR-induced hematopoietic injury, particularly the hematopoietic stem cell (HSC) injury. In this study, we explored the potential role of TF in IR-induced HSC injury and the underlying mechanism in a total body irradiation (TBI) mouse model. Our results showed that TF improved survival of irradiated wild-type mice and ameliorated TBI-induced hematopoietic injury by attenuating myelosuppression and myeloid skewing, increasing HSC frequency, and promoting reconstitution of irradiated HSCs. Furthermore, TF inhibited TBI-induced HSC senescence. These effects of TF were associated with a decline in ROS levels and DNA damage in irradiated HSCs. TF reduced oxidative stress mainly by up-regulating nuclear factor erythroid 2-related factor 2 (NRF2) and its downstream targets in irradiated Lineage-c-kit+ positive cells. However, TF failed to improve the survival, to increase HSC frequency and to reduce ROS levels of HSCs in irradiated Nrf2-/- mice. These findings suggest that TF ameliorates IR-induced HSC injury via the NRF2 pathway. Therefore, TF has the potential to be used as a radioprotective agent to ameliorate IR-induced hematopoietic injury.Ionizing radiation (IR) increases reactive oxygen species (ROS) levels in hematopoietic stem cells (HSCs) and the oxidative stress induces DNA damage, resulting in an increase in p16Ink4a expression. Theaflavin (TF) inhibits ROS production and DNA damage, and down-regulates p16Ink4a expression in HSCs. TF promotes NRF2 transportation into nucleus where it binds to the antioxidant response element (ARE), leading to the transcriptional activation of hemeoxygenase 1 (HO1), NAD (P) H: quinine oxidoreductase 1 (NQO1) and superoxide dismutase-2 (SOD2). The up-regulation of these antioxidant enzymes reduces the oxidative stress in HSCs. Consequently, TF ameliorates IR-induced hematopoietic injury of wild-type mice by increasing HSC reserve and reconstitution, and inhibiting skewed differentiation of HSCs and HSC senescence.TF scavenges ROS and inhibits DNA damage in irradiated HSCs.TF inhibits IR-induced HSC senescence.TF activates the NRF2 pathway in irradiated HSCs.TF-mediated protection against IR is abrogated by NRF2 deficiency.