Harbin Medical University, Harbin, 150086, Heilongjiang, China.
Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, Heilongjiang, China.
Mol Med. 2024 Sep 13;30(1):150. doi: 10.1186/s10020-024-00923-7.
Cis-dichlorodiammineplatinum(II) (CDDP), while widely utilized in tumor therapy, results in toxic side effects that patients find intolerable. The specific mechanism by which CDDP inflicts ovarian damage remains unclear. This study aimed to explore the involvement of ferrostatin-1 (FER-1) and ferroptosis in CDDP-induced ovarian toxicity. This study established models of CDDP-induced injury in granulosa cells (GCs) and rat model of premature ovarian failure (POF). CCK-8 assessed the effects of CDDP and FER-1 on GC viability. FerroOrange and Mito-FerroGreen, DCFH-DA and MitoSox-Red, Rhodamine 123 and Transmission electron microscopy (TEM) measured Fe, reactive oxygen species (ROS), mitochondrial membrane potential and the mitochondrial morphology in GC cells, respectively. Serum hormone levels; organ indices; malondialdehyde, superoxide dismutase, and glutathione analyses; and western blotting were performed to examine ferroptosis's role in vitro. Molecular docking simulation was evaluated the interaction between FER-1 and GPX4 or FER-1 and NRF2. Molecular docking simulations were conducted to evaluate the interactions between FER-1 and GPX4, as well as FER-1 and NRF2. The findings revealed that CDDP-induced ovarian toxicity involved iron accumulation, increased ROS accumulation, and mitochondrial dysfunction, leading to endocrine disruption and tissue damage in rats. These changes correlated with NRF2, HO-1, and GPX4 levels. However, FER-1 decreased the extent of ferroptosis. Thus, ferroptosis appears to be a crucial mechanism of CDDP-induced ovarian injury, with GPX4 as potential protective targets.
顺式-二氯二氨合铂（CDDP）虽然广泛应用于肿瘤治疗，但会导致患者无法忍受的毒性副作用。CDDP 引起卵巢损伤的确切机制尚不清楚。本研究旨在探讨铁蛋白-1（FER-1）和铁死亡在 CDDP 诱导的卵巢毒性中的作用。本研究建立了 CDDP 诱导的颗粒细胞（GC）损伤模型和大鼠卵巢早衰（POF）模型。CCK-8 评估 CDDP 和 FER-1 对 GC 活力的影响。用 FerroOrange 和 Mito-FerroGreen、DCFH-DA 和 MitoSox-Red、罗丹明 123 和透射电子显微镜（TEM）分别检测 GC 细胞中的铁、活性氧（ROS）、线粒体膜电位和线粒体形态。测定血清激素水平、器官指数、丙二醛、超氧化物歧化酶和谷胱甘肽分析；以及 Western blot 用于体外研究铁死亡的作用。进行分子对接模拟以评估 FER-1 与 GPX4 或 FER-1 与 NRF2 之间的相互作用。进行分子对接模拟以评估 FER-1 与 GPX4 以及 FER-1 与 NRF2 之间的相互作用。研究结果表明，CDDP 诱导的卵巢毒性涉及铁积累、ROS 积累增加和线粒体功能障碍，导致大鼠内分泌失调和组织损伤。这些变化与 NRF2、HO-1 和 GPX4 水平相关。然而，FER-1 降低了铁死亡的程度。因此，铁死亡似乎是 CDDP 诱导的卵巢损伤的关键机制，GPX4 可能是潜在的保护靶点。
