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- Title
Dietary ketone body–escalated histone acetylation in megakaryocytes alleviates chemotherapy-induced thrombocytopenia.
- Authors
Xie, Sisi; Jiang, Chenyu; Wu, Meng; Ye, Ying; Wu, Biying; Sun, Xiaoting; Lv, Xue; Chen, Ruibo; Yu, Wen; Sun, Qi; Wu, Yuting; Que, Rongliang; Li, Huilan; Yang, Ling; Liu, Wen; Zuo, Ji; Jensen, Lasse D.; Huang, Guichun; Cao, Yihai; Yang, Yunlong
- Abstract
Chemotherapy-induced thrombocytopenia (CIT) is a severe complication in patients with cancer that can lead to impaired therapeutic outcome and survival. Clinically, therapeutic options for CIT are limited by severe adverse effects and high economic burdens. Here, we demonstrate that ketogenic diets alleviate CIT in both animals and humans without causing thrombocytosis. Mechanistically, ketogenic diet–induced circulating β-hydroxybutyrate (β-OHB) increased histone H3 acetylation in bone marrow megakaryocytes. Gain- and loss-of-function experiments revealed a distinct role of 3-β-hydroxybutyrate dehydrogenase (BDH)–mediated ketone body metabolism in promoting histone acetylation, which promoted the transcription of platelet biogenesis genes and induced thrombocytopoiesis. Genetic depletion of the megakaryocyte-specific ketone body transporter monocarboxylate transporter 1 (MCT1) or pharmacological targeting of MCT1 blocked β-OHB–induced thrombocytopoiesis in mice. A ketogenesis-promoting diet alleviated CIT in mouse models. Moreover, a ketogenic diet modestly increased platelet counts without causing thrombocytosis in healthy volunteers, and a ketogenic lifestyle inversely correlated with CIT in patients with cancer. Together, we provide mechanistic insights into a ketone body–MCT1–BDH–histone acetylation–platelet biogenesis axis in megakaryocytes and propose a nontoxic, low-cost dietary intervention for combating CIT. Ketones for chemo: Ketones for chemoChemotherapy can reduce platelet counts in patients with cancer, in turn limiting treatment efficacy. Xie et al. report that ketogenesis-induced β-hydroxybutyrate mitigated this chemotherapy-induced thrombocytopenia by altering histone acetylation and gene transcription to promote platelet production. A ketogenic diet alleviated thrombocytopenia in mouse models treated with chemotherapy, and modestly increased platelet counts in healthy volunteers, suggesting potential relevance for clinical treatment. —CAC
- Subjects
HISTONE acetylation; PLATELET count; KETONES; ORGANELLE formation; MEGAKARYOCYTES; MONOCARBOXYLATE transporters
- Publication
Science Translational Medicine, 2022, Vol 14, Issue 673, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abn9061