Exogenous creatine supplementation promotes tumor metastasis via megakaryocyte creatine kinase B-STAT5B signaling

ABSTRACT: Creatine supplementation is widely used in sports and increasingly popular among exercising individuals. Although the physiological role of creatine has been extensively studied, the creatine biology in pathological status remains poorly understood. Here we report that exogenous creatine supplementation promotes tumor metastasis via an unexpected platelet activation mechanism in various mouse models and humans. Mechanistically, creatine supplementation increases megakaryocyte creatine concentration and upregulates creatine kinase B (CKB). Unbiased phosphoproteomics reveals that a CKB downstream non-canonical STAT5B phosphorylation instigates various platelet functional genes including purinergic receptor P2Y12 and glycoprotein VI platelet, leading to hyperactive, metastasis-promoting platelets. Megakaryocyte-specific knockout of the creatine transporter Slc6a8 or Stat5b, as well as pharmacological inhibition of STAT5 ablates the creatine-augmented hyperactive platelets and prevents consequent metastasis in mouse models. Importantly, supplement of creatine in healthy volunteers results in hyperactive peripheral platelets that increase metastasis risks. Together, our study sheds novel mechanistic insights into the creatine-induced metastasis risk and provides a new anti-metastatic therapeutic paradigm by targeting megakaryocyte creatine metabolism.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Megakaryocyte, Cell Culture

DISEASE(S): Myeloproliferative Neoplasm

SUBMITTER: LIU HUA  

LAB HEAD: Yunlong Yang

PROVIDER: PXD065649 | Pride | 2026-04-27

REPOSITORIES: Pride