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.

Despite breakthroughs in modern medical care, the incidence of cardiovascular disease (CVD) is even more prevalent globally. Increasing epidemiologic evidence indicates that emerging cardiovascular risk factors arising from the modern lifestyle, including psychosocial stress, sleep problems, unhealthy diet patterns, physical inactivity/sedentary behavior, alcohol consumption, and tobacco smoking, contribute significantly to this worldwide epidemic, while its underpinning mechanisms are enigmatic. Hematological and immune systems were recently demonstrated to play integrative roles in linking lifestyle to cardiovascular health. In particular, alterations in hematopoietic stem cell (HSC) homeostasis, which is usually characterized by proliferation, expansion, mobilization, megakaryocyte/myeloid-biased differentiation, and/or the pro-inflammatory priming of HSCs, have been shown to be involved in the persistent overproduction of pro-inflammatory myeloid leukocytes and platelets, the cellular protagonists of cardiovascular inflammation and thrombosis, respectively. Furthermore, certain lifestyle factors, such as a healthy diet pattern and physical exercise, have been documented to exert cardiovascular protective effects through promoting quiescence, bone marrow retention, balanced differentiation, and/or the anti-inflammatory priming of HSCs. Here, we review the current understanding of and progression in research on the mechanistic interrelationships among lifestyle, HSC homeostasis, and cardiovascular health. Given that adhering to a healthy lifestyle has become a mainstream primary preventative approach to lowering the cardiovascular burden, unmasking the causal links between lifestyle and cardiovascular health from the perspective of hematopoiesis would open new opportunities to prevent and treat CVD in the present age.