淫羊藿苷通过激活Nrf 2/ARE通路抑制铁凋亡减轻顺铂诱导的卵巢早衰

Icariin alleviates cisplatin-induced premature ovarian failure by inhibiting ferroptosis through activation of the Nrf2/ARE pathway      

淫羊藿苷通过激活Nrf 2/ARE通路抑制铁凋亡减轻顺铂诱导的卵巢早衰

Authors: Li F, Zhu F, Wang S, Hu H, Zhang D, He Z, Chen J, Li X, Cheng L, Zhong F.

Source：Sci Rep. 2024 Jul 27;14(1):17318. doi: 10.1038/s41598-024-67557-x.

Abstract

Cisplatin is a widely used chemotherapeutic drug that can induce ovarian damage. Icariin (ICA), a natural antioxidant derived from Epimedium brevicornum Maxim., has been found to protect against organ injury. The aim of the present study was to investigate whether ICA can exert an ovarian-protective effect on cisplatin induced premature ovarian failure (POF) and the underlying mechanism involved. The preventive effect of ICA was evaluated using body weight, the oestrous cycle, ovarian histological analysis, and follicle counting. ICA treatment increased body weight, ovarian weight, and the number of follicles and improved the oestrous cycle in POF mice. ICA reduced cisplatin-induced oxidative damage and upregulated the protein expression levels of Nrf2, GPX4 and HO-1. Moreover, ICA reduced the expression levels of Bax and γH2AX and inhibited ovarian apoptosis. In addition, ICA activated the Nrf2 pathway in vitro and reversed changes in the viability of cisplatin-induced KGN cells, reactive oxygen species (ROS) levels, lipid peroxidation, and apoptosis, and these effects were abrogated when Nrf2 was knocked down or inhibited. Molecular docking confirmed that ICA promotes the release of Nrf2 by competing with Nrf2 for binding to Keap1. The inhibitory effects of ICA on cisplatin-induced oxidative stress, ferroptosis, and apoptosis may be mediated by its modulatory effects on the Nrf2 pathway, providing a novel perspective on the potential mechanisms by which ICA prevents POF.

Keywords: Ferroptosis; Icariin; Nrf2; Ovarian damage.

摘要

顺铂是一种广泛使用的化疗药物，可引起卵巢损伤。淫羊藿苷（Icariin，伊卡）是一种来源于淫羊藿的天然抗氧化剂，已经发现其可以保护器官免受损伤。本研究旨在探讨伊卡对顺铂诱导的卵巢早衰（POF）的保护作用及其机制。通过体重、发情周期、卵巢组织学分析和卵泡计数来评价伊卡的预防效果。伊卡治疗增加POF小鼠的体重、卵巢重量和卵泡数量，并改善发情周期。伊卡可降低顺铂诱导的氧化损伤，上调Nrf 2、GPX 4和HO-1蛋白表达水平。伊卡还能降低Bax和γ H2 AX的表达，抑制卵巢细胞凋亡。此外，伊卡在体外激活Nrf 2通路，逆转顺铂诱导的KGN细胞活力、活性氧（ROS）水平、脂质过氧化和细胞凋亡的变化，当Nrf 2被敲低或抑制时，这些作用被废除。分子对接证实伊卡通过与Nrf 2竞争结合Keap 1促进Nrf 2的释放。伊卡对顺铂诱导的氧化应激、铁凋亡和细胞凋亡的抑制作用可能是通过其对Nrf 2通路的调节作用介导的，这为伊卡预防POF的潜在机制提供了新的视角。

关键词：铁缺乏症;淫羊藿苷; Nrf 2;卵巢损害