Given the high concentration of iron in the micro-environment of ovarian endometriosis, it is plausible to hypothesize that ectopic endometrial cells may be more susceptible to undergoing ferroptosis. Manipulation of ferroptosis has been explored as a potential therapeutic strategy to treat related diseases. In this study, we examined the impact on ectopic endometrial stromal cells (EESCs) of iron overload and an inducer of ferroptosis. We found that the iron concentration in the ovarian endometriosis was much higher than control samples. Treatment of cultured EESCs with ferric ammonium citrate (FAC) increase the sensitivity to undergo ferroptosis. By analyzing the RNA-seq results, it was discovered that zeste 2 polycomb repressive complex 2 subunit (EZH2) was significantly downregulated in ferroptosis induced EESCs. Moreover, overexpression of EZH2 effectively prevented the induction of ferroptosis. In addition, the activity or expression of EZH2 is directly and specifically inhibited by the methyltransferase inhibitor GSK343, which raises the sensitivity of stromal cells to ferroptosis. Taken together, our findings revealed that EZH2 act as a suppressor in the induced cell ferroptosis through a PRC2-independent methyltransferase mechanism. Therefore, blocking EZH2 expression and inducing ferroptosis may be effective treatment approaches for ovarian endometriosis.

中文翻译：

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铁过载通过 EZH2 的 PRC2 独立功能增加子宫内膜异位基质细胞对铁死亡的敏感性

鉴于卵巢子宫内膜异位症的微环境中铁浓度较高，推测异位子宫内膜细胞可能更容易发生铁死亡是合理的。铁死亡的操纵已被探索作为治疗相关疾病的潜在治疗策略。在这项研究中，我们研究了铁过载和铁死亡诱导剂对异位子宫内膜基质细胞（EESC）的影响。我们发现卵巢子宫内膜异位症样本中的铁浓度远高于对照样本。用柠檬酸铁铵 (FAC) 处理培养的 EESC 可增加发生铁死亡的敏感性。通过分析RNA-seq结果，发现zeste 2多梳抑制复合物2亚基（EZH2）在铁死亡诱导的EESC中显着下调。此外，EZH2的过度表达有效地阻止了铁死亡的诱导。此外，EZH2的活性或表达被甲基转移酶抑制剂GSK343直接、特异性抑制，从而提高了基质细胞对铁死亡的敏感性。综上所述，我们的研究结果表明，EZH2 通过不依赖 PRC2 的甲基转移酶机制在诱导的细胞铁死亡中发挥抑制作用。因此，阻断EZH2表达并诱导铁死亡可能是卵巢子宫内膜异位症的有效治疗方法。