With the widespread application of nuclear technology across various fields, ionizing radiation-induced injuries are becoming increasingly common. The bone marrow (BM) hematopoietic tissue is a primary target organ of radiation injury. Recent researches have confirmed that ionizing radiation-induced hematopoietic dysfunction mainly results from BM hematopoietic stem cells (HSCs) injury. Additionally, disrupting and reshaping BM microenvironment is a critical factor impacting both the injury and regeneration of HSCs post radiation. However, the regulatory mechanisms of ionizing radiation injury to BM HSCs and their microenvironment remain poorly understood, and prevention and treatment of radiation injury remain the focus and difficulty in radiation medicine research. In this review, we aim to summarize the effects and mechanisms of ionizing radiation-induced injury to BM HSCs and microenvironment, thereby enhancing our understanding of ionizing radiation-induced hematopoietic injury and providing insights for its prevention and treatment in the future.

Myelosuppression is a common and intractable side effect of cancer therapies including radiotherapy and chemotherapy, while the underlying mechanism remains incompletely understood. Here, using a mouse model of radiotherapy-induced myelosuppression, we show that inorganic phosphate (Pi) metabolism is acutely inhibited in hematopoietic stem cells (HSCs) during irradiation-induced myelosuppression, and closely correlated with the severity and prognosis of myelosuppression. Mechanistically, the acute Pi metabolic inhibition in HSCs results from extrinsic Pi loss in the bone marrow niche and the intrinsic transcriptional suppression of soluble carrier family 20 member 1 (SLC20A1)-mediated Pi uptake by p53. Meanwhile, Pi metabolic inhibition blunts irradiation-induced Akt hyperactivation in HSCs, thereby weakening its ability to counteract p53-mediated Pi metabolic inhibition and the apoptosis of HSCs and consequently contributing to myelosuppression progression. Conversely, the modulation of the Pi metabolism in HSCs via a high Pi diet or renal Klotho deficiency protects against irradiation-induced myelosuppression. These findings reveal that Pi metabolism and HSC survival are causally linked by the Akt/p53–SLC20A1 axis during myelosuppression and provide valuable insights into the pathogenesis and management of myelosuppression.