Reproductive Medical Center, Renmin Hospital of Wuhan University, Wuhan, China; Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, China.
Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China.
Free Radic Biol Med. 2024 Nov 1;224:707-722. doi: 10.1016/j.freeradbiomed.2024.09.033. Epub 2024 Sep 24.
Recently, the potential association between polycystic ovary syndrome (PCOS) development and progression and ferroptosis has garnered attention. Increasing evidence suggests that targeting ferroptosis may be an effective strategy for treating PCOS. First, we observed that the expression of the ferroptosis regulatory molecules SLC7A11, GPX4, and FTH1 was decreased in the granulosa cells (GCs) of patients with PCOS and ovarian tissues of rats with PCOS; in contrast, TFR1 expression was increased. This suggests that GC ferroptosis is involved in PCOS pathogenesis. Furthermore, bioinformatics analysis of GC datasets from patients with PCOS and PCOS clinical samples and animal model analysis revealed CD44 as a key molecule regulating ferroptosis in PCOS, which was down-regulated in GCs of PCOS patients and rats. Subsequently, molecular docking was performed to screen existing natural compounds for inhibiting ferroptosis. Dynamic simulation and cellular thermal shift assay identified platycodin D as a natural plant extract for inhibiting ferroptosis by targeting CD44 in GCs. Subsequently, a series of functional experiments revealed that platycodin D ameliorated ovarian damage in rats with PCOS. This was primarily owing to the protective effects achieved by promoting glutathione production, attenuating lipid accumulation and lipid peroxidation in GCs, inhibiting iron overload, and scavenging reactive oxygen species. In addition, western blotting and immunofluorescence staining revealed that platycodin D upregulated the expression of CD44 and SLC7A11 in GCs. Furthermore, by knocking down CD44 and SLC7A11 in vivo and in vitro, respectively, the ameliorative effect of platycodin D on ferroptosis in the GCs of rats with PCOS was reversed. Collectively, these findings suggest that platycodin D attenuates ferroptosis in GCs by activating CD44/SLC7A11 axis, thereby upregulating system X. In conclusion, platycodin D can attenuate ferroptosis in GCs by activating CD44, potentially ameliorating ovarian damage in PCOS.
最近，多囊卵巢综合征（PCOS）的发展和进展与铁死亡之间的潜在关联引起了关注。越来越多的证据表明，靶向铁死亡可能是治疗 PCOS 的有效策略。首先，我们观察到 PCOS 患者的颗粒细胞（GCs）和 PCOS 大鼠卵巢组织中，铁死亡调节分子 SLC7A11、GPX4 和 FTH1 的表达降低，而 TFR1 的表达增加。这表明 GC 铁死亡参与了 PCOS 的发病机制。此外，对来自 PCOS 患者的 GC 数据集和 PCOS 临床样本的生物信息学分析以及动物模型分析表明，CD44 是调节 PCOS 中铁死亡的关键分子，在 PCOS 患者的 GCs 中下调。随后，进行分子对接以筛选现有的天然化合物来抑制铁死亡。动态模拟和细胞热转移分析鉴定出桔梗皂苷 D 是一种通过靶向 GCs 中的 CD44 抑制铁死亡的天然植物提取物。随后，一系列功能实验表明，桔梗皂苷 D 改善了 PCOS 大鼠的卵巢损伤。这主要归因于桔梗皂苷 D 通过促进谷胱甘肽产生、减轻 GCs 中的脂质积累和脂质过氧化、抑制铁过载和清除活性氧来发挥保护作用。此外，western blot 和免疫荧光染色显示，桔梗皂苷 D 上调了 GCs 中 CD44 和 SLC7A11 的表达。此外，通过体内和体外分别敲低 CD44 和 SLC7A11，逆转了桔梗皂苷 D 对 PCOS 大鼠 GCs 中铁死亡的改善作用。总之，桔梗皂苷 D 通过激活 CD44/SLC7A11 轴来减轻 GCs 中的铁死亡，从而上调系统 X。综上所述，桔梗皂苷 D 通过激活 CD44 来减轻 GCs 中的铁死亡，可能改善 PCOS 中的卵巢损伤。
