Abstract：
Given that the severity of the chemotherapy-induced ovarian damage, effective fertility preservation is a necessary part of the treatment process. Ferroptosis is a regulated cell death triggered by excessive phospholipid peroxidation caused by iron and the role of ferroptosis in chemotherapy-induced ovarian damage remains unclear. In this study, we demonstrated that cisplatin treatment caused the accumulation of iron ions which induced ferroptosis in ovarian tissue. And our results show that ferrostatin-1 was able to suppress the ovarian injury and granulosa cell death caused by cisplatin (Cis) in vivo and in vitro. At the same time, we observed significant changes in the expression levels of Acyl-CoA synthetase long-chain family member 4 (Acsl4) and glutathione peroxidase 4 (GPX4). Similarly, Rosiglitazone, an inhibitor of Acsl4, administration alleviated the ovary damage of the mice undergoing chemotherapy. Further mechanistic investigation showed that cisplatin increased the expression level of specificity protein 1 (SP1), and SP1 could bind to the promoter of Acsl4 to increased Acsl4 transcription. Overall, ferroptosis plays an important role in Cis induced ovarian injury, and inhibition of ferroptosis protects ovarian tissues from damage caused by cisplatin, and for the first time, we have identified the potential of Fer-1 and Rosi to protect ovarian function in female mice undergoing chemotherapy.
摘要：
鉴于化疗引起的卵巢损伤的严重程度，有效的生育力保存是治疗过程的必要部分。铁凋亡是由铁引起的过度磷脂过氧化引发的调节性细胞死亡，铁凋亡在化疗诱导的卵巢损伤中的作用尚不清楚。在这项研究中,我们证明顺铂治疗引起铁离子的积累，从而诱导卵巢组织铁凋亡。我们的结果表明，铁抑素1能够在体内和体外抑制顺铂（Cis）引起的卵巢损伤和颗粒细胞死亡。同时,我们观察到酰基辅酶A合成酶长链家族成员4（Acsl4）和谷胱甘肽过氧化物酶4（GPX4）的表达水平发生了显着变化。同样，罗格列酮,Acsl4的抑制剂，给药减轻了接受化疗的小鼠的卵巢损伤。进一步的机制研究表明，顺铂增加了特异性蛋白1（SP1）的表达水平，SP1可以与Acsl4的启动子结合以增加Acsl4的转录。总的来说,铁凋亡在CIS诱导的卵巢损伤中起重要作用,抑制铁凋亡保护卵巢组织免受顺铂引起的损害，第一次，我们已经确定了Fer-1和Rosi在接受化疗的雌性小鼠中保护卵巢功能的潜力.
