Li Shishi, Zhou Yier, Huang Qiongxiao, Fu Xiaohua, Zhang Ling, Gao Fang, Jin Zhen, Wu Limei, Shu Chongyi, Zhang Xirong, Xu Weihai, Shu Jing
Reproductive Medicine Center, Department of Reproductive Endocrinology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 310000, Hangzhou, P. R. China.
Cell Death Discov. 2021 Nov 15;7(1):355. doi: 10.1038/s41420-021-00751-2.
Endometriosis is one of the most common disorders that causes infertility in women. Iron is overloaded in endometriosis peritoneal fluid (PF), with harmful effects on early embryo development. However, the mechanism by which endometriosis peritoneal fluid affects embryonic development remains unclear. Hence, this study investigated the effect of iron overload on mouse embryos and elucidated the molecular mechanism. Iron overload in endometriosis PF disrupted blastocyst formation, decreased GPX4 expression and induced lipid peroxidation, suggesting that iron overload causes embryotoxicity and induces ferroptosis. Moreover, mitochondrial damage occurs in iron overload-treated embryos, presenting as decreased ATP levels, increased ROS levels and MMP hyperpolarization. The cytotoxicity of iron overload is attenuated by the ferroptosis inhibitor Fer-1. Furthermore, Smart-seq analysis revealed that HMOX1 is upregulated in embryo ferroptosis and that HMOX1 suppresses ferroptosis by maintaining mitochondrial function. This study provides new insight into the mechanism of endometriosis infertility and a potential target for future endometriosis infertility treatment efforts.
子宫内膜异位症是导致女性不孕的最常见疾病之一。子宫内膜异位症腹腔液（PF）中铁过载，对早期胚胎发育有有害影响。然而，子宫内膜异位症腹腔液影响胚胎发育的机制仍不清楚。因此，本研究调查了铁过载对小鼠胚胎的影响，并阐明了分子机制。子宫内膜异位症PF中的铁过载破坏了囊胚形成，降低了GPX4表达并诱导了脂质过氧化，表明铁过载导致胚胎毒性并诱导铁死亡。此外，铁过载处理的胚胎中发生线粒体损伤，表现为ATP水平降低、ROS水平升高和线粒体膜电位超极化。铁死亡抑制剂Fer-1可减轻铁过载的细胞毒性。此外，Smart-seq分析显示HMOX1在胚胎铁死亡中上调，并且HMOX1通过维持线粒体功能来抑制铁死亡。本研究为子宫内膜异位症不孕的机制提供了新的见解，并为未来子宫内膜异位症不孕治疗提供了潜在靶点。
