Department of Gynecology of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
Department of Assisted Reproduction, the First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
Cell Death Dis. 2022 Jul 4;13(7):579. doi: 10.1038/s41419-022-05037-8.
Endometriosis (EMs) occurs in approximately 50% of women with infertility. The main causes of EMs-related infertility are follicle dysplasia and reduced oocyte quality. Iron overload occurs in ovarian follicular fluid (FF) of patients with EMs, and this condition is associated with oocyte maturation disorder. However, the underlying molecular mechanism remains largely unknown. In the present study, we identified the mechanism underlying ferroptosis in ovarian granulosa cells and oocyte maturation failure in EMs based on a retrospective review of in vitro fertilization/intracytoplasmic sperm injection-frozen embryo transfer outcomes in infertile patients with EMs. Mouse granulosa cells were treated with EMs-related infertile patients' follicular fluid (EMFF) in vitro. Western blot analysis, quantitative polymerase chain reaction, fluorescence staining, and transmission electron microscopy were used to assess granulosa cells ferroptosis. The effects of exosomes were examined by nanoparticle tracking analysis, RNA-seq, and Western blot analysis. Finally, the therapeutic values of vitamin E and iron chelator (deferoxamine mesylate) in vivo were evaluated in an EMs-related infertility model. Patients with ovarian EMs experienced poorer oocyte fertility than patients with non-ovarian EMs. We observed that EMFF with iron overload-induced granulosa cell ferroptosis in vitro and in vivo. Mechanically, nuclear receptor coactivator four-dependent ferritinophagy was involved in this process. Notably, granulosa cells undergoing ferroptosis further suppressed oocyte maturation by releasing exosomes from granulosa cells. In therapeutic studies, vitamin E and iron chelators effectively alleviated EMs-related infertility models. Our study indicates a novel mechanism through which EMFF with iron overload induces ferroptosis of granulosa cells and oocyte dysmaturity in EMs-related infertility, providing a potential therapeutic strategy for EMs-related infertility.
子宫内膜异位症（EMs）发生于约 50%的不孕女性中。EMs 相关不孕的主要原因是卵泡发育不良和卵母细胞质量下降。EMs 患者的卵巢卵泡液（FF）中存在铁过载，这种情况与卵母细胞成熟障碍有关。然而，其潜在的分子机制在很大程度上尚不清楚。在本研究中，我们基于对患有 EMs 的不孕患者体外受精/胞浆内单精子注射-冷冻胚胎移植结局的回顾性研究，鉴定了 EMs 中卵巢颗粒细胞发生铁死亡和卵母细胞成熟失败的机制。体外用 EMs 相关不孕患者的 FF 处理小鼠颗粒细胞。采用 Western blot 分析、定量聚合酶链反应、荧光染色和透射电子显微镜观察颗粒细胞铁死亡情况。通过纳米颗粒跟踪分析、RNA-seq 和 Western blot 分析检测外泌体的作用。最后，在 EMs 相关不孕模型中评估维生素 E 和铁螯合剂（甲磺酸去铁胺）的体内治疗价值。患有卵巢 EMs 的患者的卵母细胞活力较非卵巢 EMs 患者差。我们观察到，铁过载诱导的 EMFF 可导致体外和体内颗粒细胞铁死亡。在机制上，核受体共激活因子 4 依赖性铁蛋白自噬参与了这一过程。值得注意的是，发生铁死亡的颗粒细胞通过从颗粒细胞中释放外泌体进一步抑制卵母细胞成熟。在治疗研究中，维生素 E 和铁螯合剂可有效缓解 EMs 相关不孕模型。本研究表明，铁过载的 EMFF 通过诱导 EMs 相关不孕中颗粒细胞铁死亡和卵母细胞发育不成熟，提供了一种潜在的 EMs 相关不孕治疗策略。
