Creatine and endometriosis. What new discoveries have scientists made, and what does this mean in practice?

Important note: The content in this article is for educational and informational purposes only. It does not constitute medical advice and should not replace an individual consultation with a gynecologist, endocrinologist, or clinical dietitian, particularly when diagnosing or treating endometriosis, adenomyosis, or other gynecological conditions.

For years, researchers have focused on estrogen, inflammation, and immune dysfunction as the main mechanisms driving endometriosis. While these remain the focus of scientific attention, recent years have seen a growing number of studies examining endometriosis through a completely different lens: cellular metabolism. One such study, published in 2024 in the journal Advanced Science, has generated considerable interest in the scientific community. It concerns creatine, a compound most people associate with sports nutrition, and its unexpected role in endometriotic cell survival.

This isn't a topic that will change your treatment tomorrow , but it is a good example of how science is gradually uncovering disease mechanisms that were previously invisible.

Why do endometrial cells survive where they shouldn't?

To understand what this study is about, it's worth taking a step back and explaining one of the fundamental paradoxes of endometriosis.

According to the most widely accepted theory, endometrial cells end up outside the uterus during retrograde menstruation, when menstrual blood flows backward through the fallopian tubes into the peritoneal cavity. This blood is rich in heme and iron. Excess iron is normally toxic to cells because it leads to oxidative stress and can trigger a specific cell death mechanism called ferroptosis.

And herein lies the mystery. If the peritoneal cavity is rich in iron and should induce ferroptosis, why do endometrial cells not only survive but also implant, proliferate, and form disease foci? What makes them resistant to the death that iron should induce?

This question is one of the key ones in research on the pathogenesis of endometriosis, and it is in this context that the topic of creatine appears.

What is ferroptosis and why is it important in endometriosis?

Ferroptosis is a relatively newly described mechanism of programmed cell death that differs from classical apoptosis. It is not triggered by typical apoptotic signals, but by an excess of free iron ions within the cell. Excess iron participates in the Fenton reaction, which produces reactive oxygen species. These, in turn, damage cell membrane lipids in a process called lipid peroxidation. When the damage exceeds the cell's ability to repair itself, the cell dies.

In a healthy body, ferroptosis is a defense mechanism because it destroys cells that have become dangerous to the body. Cancer research has observed that cancer cells often develop mechanisms of resistance to ferroptosis, allowing them to survive in difficult conditions and continue to proliferate. Endometriosis , although a benign disease, shows certain similarities to this pattern, as endometrial cells in diseased lesions are able to survive in an environment that should eliminate them.

Studying the ability of these cells to avoid ferroptosis is a new and promising direction in understanding why endometriosis develops in the first place.

What did scientists observe in the 2024 study?

Chen and colleagues' team in Shanghai conducted a metabolomics analysis of endometrial cells collected from women with and without endometriosis. Metabolomics is a technique that allows for the measurement of the concentrations of hundreds of small chemical molecules in a cell simultaneously and allows for comparisons of differences between groups.

The results showed that creatine concentrations in ectopic cells, i.e., those forming endometriosis foci, and in the peritoneal fluid of women with endometriosis were significantly higher than in the cells and fluid of women without the disease. Importantly, further analysis revealed that this creatine is not derived from outside sources. Endometrial cells in disease foci produce more creatine themselves because they have higher activity of the GATM enzyme, a key enzyme in its synthesis.

This means that creatine accumulating in endometriosis foci is a product of the metabolism of the disease cells themselves, and not the effect of diet or supplementation.

The researchers then asked what this creatine did. In laboratory experiments, they demonstrated that creatine in an iron-rich environment increased the survival of endometrial cells. Cells treated with creatine had lower concentrations of free iron ions within the cells, lower levels of reactive oxygen species, and lower levels of lipid peroxidation products. Simply put, creatine helped the cells resist the ferroptosis that should eliminate them.

How Creatine Inhibits Ferroptosis: The PrP Mechanism

The next step was to determine how creatine does this. The researchers used a technique called DARTS, which identifies the proteins to which the test substance binds. The results pointed to the PrP protein, more commonly known as prion protein.

PrP acts as an enzyme in the cell that aids in iron transport by catalyzing the conversion of trivalent iron to divalent iron, a step necessary for cellular uptake. The more active PrP, the more iron is transported into the cell and the greater the risk of ferroptosis.

The researchers' hypothesis is as follows: creatine binds to the active site of PrP and blocks its activity. Less active PrP means less iron within the cell, fewer reactive oxygen species, and a lower risk of ferroptosis. By producing more creatine, the endometrial cell effectively protects itself from the mechanism that should eliminate it.

In a mouse model, researchers confirmed that creatine administration increased the number, weight, and volume of endometriosis lesions. Mice with higher PrP expression had fewer lesions, and adding creatine reversed this effect.

What is certain in these results and what requires confirmation?

This study is pioneering but still preliminary, so it is worth knowing both dimensions.

In terms of strengths, the study combines analysis of patient samples with cell experiments and an animal model, providing three levels of support for the hypothesis. It clearly demonstrates that creatine accumulates endogenously in disease sites, and its association with cell survival in an iron-rich environment is biologically consistent with what is known about ferroptosis.

Limitations include small patient groups, which makes generalizing the results difficult. Creatine concentrations used in laboratory experiments were somewhat higher than those measured in the patients' peritoneal fluid. The proposed mechanism of creatine binding to PrP requires independent biochemical verification using purified proteins. The scientific community, including a commentary published in 2026 by Marco Machado, has highlighted these issues, and the study authors agreed with them on several points while defending the main conclusions.

This is the normal course of the scientific process, as research opens up questions, commentary points out weaknesses, and subsequent work validates them. The fact that controversy has arisen doesn't mean the results are flawed, but it does mean that science is working as it should.

What does this mean for women with endometriosis in practice?

Honestly, at this stage it doesn't change anything in your daily routine.

The results of the study by Chen et al. do not constitute a basis for eliminating creatine from the diet. The creatine described in this study is produced endogenously by the disease cells themselves, and its concentrations in the peritoneal fluid of women with endometriosis were elevated regardless of their diet. A relationship between dietary or supplemental creatine and creatine levels in endometriosis lesions was not the subject of this study and cannot be assumed based on this information.

What this research opens up is a new therapeutic direction. If further work confirms that endometrial cell resistance to ferroptosis is driven by the creatine-PrP pathway, both the creatine synthesis enzymes and the PrP protein itself could become targets for future therapies. However, these therapies are not available today or in the near future. This is an area of ​​basic research that must undergo numerous stages of validation before any clinical application can be achieved.

The value of these discoveries lies elsewhere: each new window into the mechanisms of the disease brings us closer to a better understanding of why endometriosis develops and why it is so difficult to treat. This is a foundation upon which new therapeutic options may emerge in the future.

Sources

Chen S, Liu X, Zhang Y. Creatine promotes endometriosis by inducing ferroptosis resistance via suppression of PrP. Advanced Science, Volume 11, Number 4, Pages 2304112, December 2024.

Machado M. Reassessing the proposed creatine PrP axis in endometriosis, methodological and mechanistic considerations. Advanced Science, Volume 13, Number 2, Pages 2501042, February 2026.

Chen S, Liu X, Zhang Y. Reply to Reassessing the proposed creatine PrP axis in endometriosis, methodological and mechanistic considerations. Advanced Science, Volume 13, Number 2, Pages 2501043, February 2026.

Wojtyła C, Bizoń A, Wdowiak A. Metabolome analysis as a potential source of endometriosis biomarkers with the use of multiomics approach in its diagnosis. Scientific Reports, volume 15, number 1, pages 8412, March 2025.

ESHRE Endometriosis Guideline Development Group. Endometriosis, guideline of the European Society of Human Reproduction and Embryology. ESHRE Guidelines Office, Central Building, Grimbergen, January 2022.