Endometriosis an important cause of female infertility and seriously impact physical and psychological health of patients. Endometriosis is now considered to be a public health problem that deserves in-depth investigation, especially the etiopathogenesis of endometriosis-associated infertility. We aimed to illuminate the etiopathogenesis of endometriosis-associated infertility that involve excessive oxidative stress (OS) induced pathological changes of ovary cumulus granulosa cell (GCs). Senescence-associated β-galactosidase (SA β-gal) activity in GCs from endometriosis patients, soluble isoform of advanced glycation end products receptor (sRAGE) expression in follicular fluid from endometriosis patients and differentially expressed senescence-associated secretory phenotype factors (IL-1β, MMP-9, KGF and FGF basic protein) are all useful indexes to evaluate oocyte retrieval number and mature oocyte number. RNA-sequencing and bioinformatics analysis indicated senescent phenotype of endometriosis GCs and aggravated endoplasmic reticulum (ER) stress in endometriosis GCs. Targeting ER stress significantly alleviated OS-induced GCs senescence as well as mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) reduction in GCs. Moreover, melatonin administration rescued OS-enhanced ER stress, cellular senescence, and MMP and ATP abnormities of endometriosis GCs in vitro and in vivo. In conclusion, our results indicated excessive reactive oxygen species induces senescence of endometriosis GCs via arouse ER stress, which finally contributes to endometriosis-associated infertility, and melatonin may represent a novel adjuvant therapy strategy for endometriosis-associated infertility.

子宫内膜异位症是女性不育症的重要原因，严重影响患者的身心健康。子宫内膜异位症现在被认为是一个公共卫生问题，值得深入研究，尤其是与子宫内膜异位症相关的不育症的病因。我们旨在阐明子宫内膜异位症相关不育的病因，其中涉及过度的氧化应激（OS）诱导卵巢卵丘颗粒细胞（GCs）的病理变化。子宫内膜异位患者GC中的衰老相关β-半乳糖苷酶（SAβ-gal）活性，子宫内膜异位患者卵泡液中晚期糖基化终产物受体（sRAGE）表达的可溶性同工型以及差异表达的衰老相关分泌表型因子（IL-1β） ，MMP-9，KGF和FGF碱性蛋白）都是评估卵母细胞取回数和成熟卵母细胞数的有用指标。RNA测序和生物信息学分析表明子宫内膜异位症GCs的衰老表型和子宫内膜异位症GCs的内质网（ER）应激加剧。靶向内质网应激可显着缓解OS诱导的GC衰老以及GC中线粒体膜电位（MMP）和三磷酸腺苷（ATP）减少。此外，褪黑激素给药可挽救子宫内膜异位症GC的OS增强的ER应激，细胞衰老以及MMP和ATP异常 靶向内质网应激可显着缓解OS诱导的GC衰老以及GC中线粒体膜电位（MMP）和三磷酸腺苷（ATP）减少。此外，褪黑激素给药可挽救子宫内膜异位症GC的OS增强的ER应激，细胞衰老以及MMP和ATP异常 靶向内质网应激可显着缓解OS诱导的GC衰老以及GC中线粒体膜电位（MMP）和三磷酸腺苷（ATP）减少。此外，褪黑激素给药可挽救子宫内膜异位症GC的OS增强的ER应激，细胞衰老以及MMP和ATP异常体外和体内。总之，我们的结果表明，过量的活性氧通过引起内质网应激而诱导子宫内膜异位症的衰老，最终促成子宫内膜异位症相关的不育症，而褪黑素可能代表子宫内膜异位症相关性不孕症的新型辅助治疗策略。