Study Opens New Therapeutic Avenue for Ovarian Endometriosis

Blocking the expression of an enzyme called EZH2 or inducing ferroptosis may be an effective treatment option for ovarian endometriosis

Key Points

Highlights: 

• EZH2, the functional enzymatic component of a protein called PRC2 acts as a suppressor in the induced cell ferroptosis.

Importance:

• Blocking the expression of this enzyme or inducing ferroptosis may be effective in treating ovarian endometriosis, which is more susceptible to ferroptosis.

What’s done here:

• Researchers analyzed the effect of iron overload as an inducer of ferroptosis on ectopic endometrial stromal cells (n=19) and on eutopic endometrial specimens (n=14)

Key results:

• The concentration of iron was higher in ovarian endometriosis.
• Treatment of cultured ectopic endometrial stromal cells with ferric ammonium citrate increased their sensitivity to undergoing ferroptosis.
• EZH2 was significantly downregulated in ferroptosis-induced-ectopic endometrial stromal cells.
• EZH2 overexpression effectively prevented ferroptosis.
• The methyltransferase inhibitor GSK343 directly and specifically inhibited the activity or expression of EZH2, raising the sensitivity of stromal cells to ferroptosis. 

Lay Summary

Ferroptosis is a recently discovered cell death characterized by iron dependence, lipid peroxidation, and membrane damage. Studies show that erastin induces ferroptosis in ectopic endometrial stromal cells, reducing ectopic lesions.

Enhancer of zeste homolog 2 (EZH2), a component of the polycomb repressive complex 2 (PRC2), suppresses ferroptosis independent of PRC2, according to a new study published in The International Journal of Biochemistry & Cell Biology. It does so via a methyltransferase mechanism, the study also showed.

Based on these findings, the authors concluded that blocking the expression of EZH2 and inducing ferroptosis may be effective treatment approaches in ovarian endometriosis since ectopic endometrial cells are thought to be more susceptible to ferroptosis. Manipulation ferroptosis as a potential therapeutic strategy has already been explored as a treatment option in diseases related to endometriosis.

In the present study a team of researchers led by Dr. Lina Chen from the Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, and Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education at Xi'an Jiaotong University in Xi'an, China assessed the effect of iron overload on ectopic endometrial stromal cells and as an inducer of ferroptosis.

They reported that the concentration of iron in ovarian endometriosis was higher than in control samples. 

When they treated cultured ectopic endometrial stromal cells with ferric ammonium citrate, the researchers saw that their sensitivity to undergoing ferroptosis increased. Then, via RNA-sequencing experiments, they found that EZH2 was significantly downregulated in ectopic endometrial stromal cells in which ferroptosis was induced. In a reverse experiment, they showed that overexpressing EZH2 prevented ferroptosis in an effective manner.  Finally, they showed that the activity or expression of EZH2 was directly and specifically inhibited by the methyltransferase inhibitor GSK343, raising the sensitivity of stromal cells to ferroptosis. 

Research Source: https://pubmed.ncbi.nlm.nih.gov/38417568/