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<p>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 conditions remains poorly understood. Here we report that exogenous creatine supplementation promotes tumor metastasis via platelet activation mechanism in various mouse models and humans. Mechanistically, creatine supplementation increases megakaryocyte creatine levels and upregulates creatine kinase B (CKB). Unbiased phosphoproteomics reveals that a CKB-downstream, non-canonical STAT5B phosphorylation instigates various platelet functional genes, leading to hyperactive, metastasis-promoting platelets. Megakaryocyte-specific knockout of the creatine transporter <i>Slc6a8</i> or <i>Stat5b</i>, as well as pharmacological inhibition of STAT5, ablates the creatine-augmented platelet hyperactivity and prevents consequent metastasis in mice. Importantly, creatine supplementation in healthy volunteers results in hyperactive peripheral platelets that increase metastasis risks. Together, our study sheds mechanistic insights into the creatine-induced metastasis and provides an anti-metastatic therapeutic paradigm by targeting megakaryocyte creatine metabolism.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月15日

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  • Sisi Xie,
  • Ruibo Chen,
  • Xiaoting Sun,
  • Xiaolei Ni,
  • Yuting Wu,
  • Linli Cai,
  • Yangyi Chen,
  • Shuangming Lin,
  • Mei Rao,
  • Liling Chen,
  • Yintao Li,
  • Yanyong Xu,
  • Minfeng Chen,
  • Dongmei Zhang,
  • Shun Zhu,
  • Ling Yang,
  • Wen Liu,
  • Ji Zuo,
  • Yunlong Yang

摘要

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 conditions remains poorly understood. Here we report that exogenous creatine supplementation promotes tumor metastasis via platelet activation mechanism in various mouse models and humans. Mechanistically, creatine supplementation increases megakaryocyte creatine levels and upregulates creatine kinase B (CKB). Unbiased phosphoproteomics reveals that a CKB-downstream, non-canonical STAT5B phosphorylation instigates various platelet functional genes, 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 platelet hyperactivity and prevents consequent metastasis in mice. Importantly, creatine supplementation in healthy volunteers results in hyperactive peripheral platelets that increase metastasis risks. Together, our study sheds mechanistic insights into the creatine-induced metastasis and provides an anti-metastatic therapeutic paradigm by targeting megakaryocyte creatine metabolism.