DDO1002, an NRF2–KEAP1 inhibitor, improves hematopoietic stem cell aging and stress response

Oxidative stress diminishes the functionality of hematopoietic stem cells (HSCs) as age advances, with heightened reactive oxygen species (ROS) levels exacerbating DNA damage, cellular senescence, and hematopoietic impairment. DDO1002, a potent inhibitor of the NRF2-KEAP1 pathway, modulates the expression of antioxidant genes. Yet, the extent to which it mitigates hematopoietic decline post-total body irradiation (TBI) or in the context of aging remains to be elucidated. Our study has elucidated the role of DDO1002 in modulating NRF2 activity, which, in turn, activates the NRF2-driven antioxidant response element (ARE) signaling cascade. This activation can diminish intracellular levels of ROS, thereby attenuating cellular senescence. In addition, DDO1002 has been demonstrated to ameliorate DNA damage and avert HSC apoptosis, underscoring its potential to mitigate hematopoietic injury precipitated by TBI. Competitive transplantation assay revealed that the administration of DDO1002 can improve the reconstitution and self-renewal capacity of HSCs in aged mice. Single-cell sequencing analysis elucidated that DDO1002 treatment attenuated intracellular inflammatory signaling pathways and mitigated ROS pathway in aged HSCs, suggesting its potential to restore the viability of these cells. Consequently, DDO1002 effectively activated the NRF2-ARE pathway, delaying cellular senescence and ameliorating impaired hematopoiesis, thereby demonstrating its potential as a therapeutic agent for age-related hematopoietic disorders.