Post-irradiation dietary restriction impairs hematopoiesis via inhibition of the pentose phosphate pathway in hematopoietic stem and progenitor cells

Although the clinical observation of hematologic toxicity related to radiotherapy has been recognized for a long time, the underlying mechanisms remain to be fully explored. Here, we established a mouse model of reduced dietary intake (dietary restriction, DR, 30% reduction in food intake compared to age-matched and gender-matched mice) following X-ray radiation exposure to investigate the impact of reduced dietary intake on hematopoiesis after irradiation. We found that post-irradiation DR significantly and persistently suppressed hematopoiesis and notably impaired the regenerative capacity of hematopoietic cells. Compared to ad libitum (AL) fed mice, post-irradiation DR led to sustained upregulation of the DNA damage response (DDR) signaling pathway in hematopoietic cells, even 14 days to 1 month after irradiation, along with delayed DNA repair. Further investigation revealed that DR suppressed the post-irradiation activation of the pentose phosphate pathway (PPP). Inhibition of PPP by 6-Aminonicotinamide (6-AN) in AL mice mimicked the impairment of hematopoiesis observed in DR mice, while activation of PPP by AG1 in DR mice rescued the impairment of DNA repair and hematopoiesis in these mice. Additionally, we conducted a retrospective analysis of 101 cancer patients who received pelvic radiotherapy and found that patients with lower Body Mass Index (BMI) experienced more severe reductions in white blood cells (WBCs), neutrophils, and lymphocytes. This study suggests that DR following irradiation inhibits hematopoiesis by suppressing PPP, providing a new approach to addressing radiotherapy-related myelosuppression and potentially offering solutions for improving refractory hematopoietic disorders associated with radiotherapy.