Dietary restriction mitigates 5-fluorouracil-induced thrombocytopenia in aged mice via mitochondrial potentiation in hematopoietic stem cells and megakaryocyte progenitors.

With population aging, chemotherapy-induced thrombocytopenia (CIT) is a severe complication in elderly cancer patients, yet effective preventive and therapeutic strategies remain limited. Here, we demonstrate that dietary restriction (DR) significantly mitigates 5-fluorouracil (5-FU)-induced thrombocytopenia and promotes platelet recovery in both young and aged mice. Mechanistically, DR improves mitochondrial homeostasis in hematopoietic stem and progenitor cells and enhances their hematopoietic reconstitution capacity. This preconditioning facilitates mitochondrial activation after chemotherapy, thereby promoting megakaryocytic lineage recovery. Pharmacological mitochondrial activation in ad libitum-fed mice mimics the protective effects of DR, whereas mitochondrial inhibition in DR-treated mice markedly attenuates these benefits. Clinically, cancer patients with lower pre-chemotherapy body mass index ([BMI] 18.5-22.95 kg/m2) showed a lower incidence of CIT following 5-FU treatment than those with higher BMI. Together, we show that short-term DR significantly mitigates CIT and that targeting mitochondria may represent a novel therapeutic strategy for CIT in elderly cancer patients.