Creatine supplements may boost tumor metastasis through megakaryocyte signaling pathways

In a finding that challenges a popular sports supplement’s reputation, researchers report that exogenous creatine can accelerate tumor metastasis through an unexpected signaling route. The work, published in Nature Communications (2026), links creatine supplementation to changes in how megakaryocytes—blood-cell precursors best known for clotting—communicate with cancer cells.

The study focuses on a pathway centered on creatine kinase B (CKB), an enzyme that reshapes cellular energy dynamics. Using experimental models that track metastatic spread, the authors show that adding creatine to the systemic environment increases metastatic burden, suggesting a causal role rather than a mere correlation.

Mechanistically, the results propose a two-stage trigger. First, creatine availability enhances CKB-related activity in megakaryocytes, altering metabolite flux and downstream signaling capacity. Second, these megakaryocytes activate a pro-metastatic communication program that culminates in STAT5B signaling within tumor-associated contexts.

STAT5B is a transcription factor commonly associated with cytokine-responsive gene regulation. Here, the authors describe phosphorylation and nuclear activity changes consistent with a STAT5B-driven transcriptional shift. The shift appears to promote tumor phenotypes favorable for survival in circulation and colonization at distant sites.

To establish pathway specificity, the team employed genetic and pharmacologic perturbations targeting components of the CKB–STAT5B axis. Disrupting this signaling reduced the creatine-linked increase in metastatic outcomes, strengthening the causal link between the supplement-derived energy pathway and metastatic progression.

The authors also report that relevant molecular markers in tumor-associated cell populations changed in parallel with metastatic readouts. These measurements support a model in which megakaryocyte signaling—rather than direct creatine effects on cancer cells alone—acts as a controlling interface for metastatic efficiency.

Taken together, the work raises safety questions for creatine use in populations at risk for cancer. While creatine has well-characterized roles in muscular energy buffering, the new data suggest that, in a tumor ecosystem, it may inadvertently enhance pro-metastatic signaling.

Importantly, the study does not claim that all creatine use will universally worsen cancer outcomes. Instead, it provides a mechanistic framework indicating that the timing, context, and microenvironmental responses could determine whether supplementation is harmless or harmful.

For clinicians and scientists, the key implication is that cancer progression may be modulated by metabolic “inputs” that reshape immune-blood cell signaling. Future work will likely determine which patient subsets and dosing ranges might matter, and whether pathway-targeted interventions could neutralize the effect without compromising energy metabolism.