Reply to “Reassessing the Proposed Creatine–PrP Axis in Endometriosis: Methodological and Mechanistic Considerations”

ABSTRACT This Correspondence is a formal response to the Comment by Dr. Machado regarding our publication “Creatine Promotes Endometriosis by Inducing Ferroptosis Resistance via Suppression of PrP.” We address several conceptual concerns raised in the Comment and clarify the physiological relevance of creatine concentrations, the methodological framework for PrP target identification, and the interpretation of human cohort data. We further provide evidence supporting creatine accumulation in endometriotic lesions and peritoneal fluid, and clarify the experimental basis for PrP target identification using integrated biochemical, computational, and functional analyses. Rather than demonstrating a direct molecular interaction, our findings instead provide convergent evidence consistent with PrP acting as a candidate functional target of creatine. We also reinforce the association between creatine exposure, ferroptosis resistance, and lesion progression, while acknowledging that definitive biochemical validation of direct binding remains to be established. Importantly, our study provides translational support for mechanistic investigations in endometriosis, rather than establishing a definitive clinical biomarker. Collectively, we highlight the metabolic significance of creatine–PrP signaling in endometriosis and discuss future directions for mechanistic and clinical validation.