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CDK4-driven ketogenesis rewires histone modification to promote leukemia

ABSTRACT: Ketogenic nutrition has shown promise as an adjunct to conventional cancer therapies, its efficacy varies across cancer types depending on their metabolic characteristics.1,2 How ketogenic metabolites affect tumorigenesis, and whether ketone metabolism becomes deregulated in cancer cells, remain incompletely understood. Using T-cell acute lymphoblastic leukemia (T-ALL) as a model, we demonstrate that the ketone body β-hydroxybutyrate (BHB) is elevated in cancer cells and exerts a strong pro-leukemogenic effect. Remarkably, the key ketogenic enzyme β-hydroxybutyrate dehydrogenase 1 (BDH1) is significantly upregulated, enabling carbohydrate-driven BHB synthesis in leukemia cells. Mechanistically, aberrant CDK4 activation enables direct phosphorylation of BDH1 and enhances its protein stability. BDH1-mediated production of BHB augments histone β-hydroxybutyrylation (Kbhb) and activates transcription of pro-leukemogenic genes. Either BDH1 deficiency or CDK4 inactivation significantly suppresses T-ALL progression in vivo. Notably, ketogenic diet markedly reduces the anti-leukemic efficacy of the clinically approved CDK4/6 inhibitor palbociclib. Together, these findings highlight how oncogenic CDK4 drives cancer cell ketogenesis through BDH1 phosphorylation and promotes tumor progression via an epigenetic mechanism. Moreover, the implementation of ketogenic nutrition in cancer therapy should be approached with caution and guided by the molecular pathogenesis of individual cancer types.

ORGANISM(S): Homo sapiens

PROVIDER: GSE311088 | GEO | 2025/12/09

REPOSITORIES: GEO

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Project description:In Alzheimer’s disease, dysfunctional microglia possess abnormal immunometabolic features that cause neuronal/synaptic damage and aggravate pathology. A critical question is how to reverse or fine-tune abnormal microglial metabolism towards beneficial immunometabolic outcomes. A major metabolic intervention strategy to raise circulating ketone levels for health benefits, such as by consumption of a ketogenic diet 1, fasting, or other approaches collectively called ketotherapeutics, has raised a great deal of interest, but its effects on microglia are not well understood. Our previous in vitro study showed that β-hydroxybutyrate (BHB), a major ketone body, reverses multiple pathological features of amyloid-β oligomer (AβO)-activated human microglia. In the current study, we tested the in vivo effects of BHB on microglia and synaptic plasticity in the 5xFAD Alzheimer’s disease mouse model. To capture the metabolic impact of BHB on microglia, we employed a “subacute” 1-week regimen of daily intraperitoneal injection of BHB (250 mg/kg), which induced brief and mild episodic (daily) ketosis. This short regimen was able to mitigate pro-inflammatory microglia activation linked to NLRP3 inflammasome formation, and reduce brain amyloid-β deposition by enhancing phagocytosis. Remarkably, this regimen mitigated the deficits of hippocampal long-term depression but not long-term potentiation, and this effect was linked to suppression of the inflammasome-generated cytokine IL-1β. Our results suggest that short-term BHB treatment may ameliorate microglial abnormalities and microglia-regulated synaptic deficits in Alzheimer’s disease. Because beneficial results were achieved with mild episodic BHB elevation alone without diet restriction and without the need of feeding a KD, our results have significant implications to human ketotherapeutics. As KDs are known for poor compliance and low sustainability due to their restrictive nature, our study opens the possibility for alternative ketogenic approaches that are less restrictive, potentially safer, and easier for compliance than a KD, such as short-term BHB injections or dietary ketone esters, a translatable form of induced ketosis.

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CDK4-driven ketogenesis rewires histone modification to promote leukemia

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