ANXA1 Inhibits Trophoblast Ferroptosis in Preeclampsia by Downregulating KISS1.

IF 3.1 2区 生物学 Q2 REPRODUCTIVE BIOLOGY
Yuzhu Rao, Shiming Tan, Jingjing Wang, Jingqiu Jia, Zemin Cai, Chunyan Wu, Peng Wu, Zuo Wang
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Abstract

Preeclampsia (PE) is a significant hypertensive disorder associated with pregnancy, impacting the health of women and children globally. It stands as one of the primary contributors to elevated morbidity and mortality rates among pregnant individuals and neonates. Recent investigations indicate a significant potential association between ferroptosis and PE. Annexin A1 (ANXA1) serves as an endogenous inhibitor of inflammation, capable of being activated by glucocorticoids, ischemia-reperfusion events, inflammatory processes, or oxidative stress. Ac2-26 is a synthetic peptide derived from the N-terminal 26 amino acids of the ANXA1 protein and retains its anti-inflammatory properties. Nevertheless, the precise regulatory mechanisms underlying ANXA1's role in PE remain to be fully elucidated. In this study, we first revealed that the increase in ferroptosis in preeclamptic placentas is accompanied by a downregulation of ANXA1 expression. Next, we established a PE-like mouse model and confirmed the presence of ferroptosis in the placentas of these mice. Ac2-26 treatment reduced placental ferroptosis and improved adverse pregnancy outcomes. Additionally, we demonstrated that targeting ANXA1 (Ac2-26) alleviates RSL3-induced trophoblast dysfunction and inhibits its promotion of intracellular lipid peroxidation. Subsequent mechanistic investigations have demonstrated that the elevation of KISS1 levels is intricately associated with ferroptosis and PE, while ANXA1 (Ac2-26) serves to inhibit KISS1 expression, thereby ultimately mitigating ferroptosis. In summary, this study presents the novel finding that elevated levels of KISS1 during pregnancy promote ferroptosis, a process that is mitigated by ANXA1 (Ac2-26) through the downregulation of KISS1 expression, thereby alleviating PE. This discovery offers a promising therapeutic strategy targeting the ferroptosis signaling pathway in PE.

ANXA1通过下调KISS1抑制子痫前期滋养细胞铁下垂。
子痫前期(PE)是一种与妊娠相关的重要高血压疾病,影响着全球妇女和儿童的健康。它是孕妇和新生儿发病率和死亡率升高的主要原因之一。最近的研究表明,铁下垂和PE之间存在显著的潜在关联。膜联蛋白A1 (ANXA1)是一种内源性炎症抑制剂,可被糖皮质激素、缺血再灌注事件、炎症过程或氧化应激激活。Ac2-26是一种合成肽,由ANXA1蛋白的n端26个氨基酸衍生而来,并保留其抗炎特性。尽管如此,ANXA1在PE中作用的确切调控机制仍有待充分阐明。在这项研究中,我们首次发现子痫前期胎盘铁下垂的增加伴随着ANXA1表达的下调。接下来,我们建立pe样小鼠模型,证实这些小鼠的胎盘中存在铁下垂。Ac2-26治疗可减少胎盘铁下垂,改善不良妊娠结局。此外,我们证明靶向ANXA1 (Ac2-26)可减轻rsl3诱导的滋养细胞功能障碍,并抑制其促进细胞内脂质过氧化。随后的机制研究表明,KISS1水平的升高与铁下垂和PE有着复杂的关系,而ANXA1 (Ac2-26)抑制KISS1的表达,从而最终减轻铁下垂。总之,本研究提出了一个新发现,妊娠期间KISS1水平升高会促进铁下垂,而ANXA1 (Ac2-26)通过下调KISS1表达来减轻这一过程,从而减轻PE。这一发现为PE中的铁下垂信号通路提供了一种有希望的治疗策略。
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来源期刊
Biology of Reproduction
Biology of Reproduction 生物-生殖生物学
CiteScore
6.30
自引率
5.60%
发文量
214
审稿时长
1 months
期刊介绍: Biology of Reproduction (BOR) is the official journal of the Society for the Study of Reproduction and publishes original research on a broad range of topics in the field of reproductive biology, as well as reviews on topics of current importance or controversy. BOR is consistently one of the most highly cited journals publishing original research in the field of reproductive biology.
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