Li Yuwen, Wu Aiwei, Jin Xinrong, Shen Haiping, Zhao Chenyan, Yi Xiao, Nie Hui, Wang Mingwei, Yin Shouchun, Zuo Hongna, Ju Zhenyu, Jiang Zhenyu, Wang Hu
Zhejiang Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, The Third People's Hospital of Deqing, Department of Cardiology, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou 311121, China.
MOE Key Laboratory of Regenerative Medicine, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China.
Life Med. 2024 Dec 12;3(6):lnae043. doi: 10.1093/lifemedi/lnae043. eCollection 2024 Dec.
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.
随着年龄的增长，氧化应激会降低造血干细胞（HSC）的功能，活性氧（ROS）水平的升高会加剧DNA损伤、细胞衰老和造血功能障碍。DDO1002是NRF2-KEAP1途径的有效抑制剂，可调节抗氧化基因的表达。然而，它在减轻全身照射（TBI）后或衰老情况下造血功能衰退的程度仍有待阐明。我们的研究阐明了DDO1002在调节NRF2活性中的作用，这反过来又激活了NRF2驱动的抗氧化反应元件（ARE）信号级联反应。这种激活可以降低细胞内ROS水平，从而减轻细胞衰老。此外，已证明DDO1002可改善DNA损伤并避免HSC凋亡，突出了其减轻TBI引发的造血损伤的潜力。竞争性移植试验表明，给予DDO1002可提高老年小鼠HSC的重建和自我更新能力。单细胞测序分析表明，DDO1002处理可减弱老年HSC中的细胞内炎症信号通路并减轻ROS通路，表明其恢复这些细胞活力的潜力。因此，DDO1002有效地激活了NRF2-ARE途径，延缓细胞衰老并改善造血功能受损，从而证明了其作为与年龄相关的造血疾病治疗剂的潜力。
