Reassessing the Proposed Creatine–PrP Axis in Endometriosis: Methodological and Mechanistic Considerations

ABSTRACT The research by Chen et al. (2024) presents an innovative hypothesis linking creatine metabolism to ferroptosis resistance in endometriotic stromal cells via PrP suppression. While conceptually valuable, methodological aspects warrant reflection. A primary concern involves the supraphysiological creatine concentrations used, whose translational relevance is questionable without pharmacokinetic data confirming these levels in the peritoneal environment, particularly in light of available clinical metabolomics data suggesting differences in creatine levels in peritoneal fluid under physiological and pathological conditions. Furthermore, the proposed direct suppression of PrP ferrireductase activity would benefit from complementary biochemical validation using purified systems and affinity measurements to consolidate the molecular mechanism. Although human samples were included, the small cohort size and lack of control for confounding variables limit the specificity of interpretation, source attribution, and the external generalizability of the findings. Finally, future studies should target endogenous creatine synthesis or transport to clarify whether creatine is a causal driver of ferroptosis resistance or simply associated with the inflammatory microenvironment. Overall, Chen et al. provide an exciting contribution; these constructive considerations aim to support future refinements that will solidify the proposed model and its clinical significance.