ACOD1/Itaconate regulates trophoblast function through the PI3K/Akt/FOLR1 axis to participate in the pathogenesis of recurrent spontaneous abortion.

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2025-10-03 DOI:10.1016/j.bcp.2025.117405

Tingting Feng, Shujuan Wu, Jianye Fang, Jinli Ding, Fujin Shen, Jing Yang

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引用次数: 0

Abstract

The pathogenesis of recurrent spontaneous abortion (RSA) remains unclear. Our research focused on Aconitate decarboxylase 1 (Acod1) and discovered its role in RSA. Western blotting, qPCR, and immunohistochemistry results indicated that Acod1 was markedly upregulated in villous tissues of RSA patients. On one hand, overexpression of Acod1 inhibited the invasion and migration abilities of trophoblast cell lines. Screening for differentially expressed genes related to cell migration, folate receptor 1 (FOLR1) was significantly downregulated after Acod1 overexpression. Overexpression of FOLR1 restored the invasion and migration abilities of trophoblast cells. On the other hand, when trophoblast cells were co-cultured with macrophages, trophoblast cells overexpressing Acod1 promoted the polarization of macrophages towards the M1 phenotype. Acod1 mainly exerted its function by catalyzing the production of excessive itaconate (ITA). Further analysis of KEGG results revealed that PI3K/Akt was the main mechanism of Acod1/Itaconate action. Overexpression of Acod1 or addition of exogenous itaconate inhibited the phosphorylation of PI3K and Akt. We also found that Acod1 was abnormally elevated in decidual macrophages, and macrophages overexpressing Acod1 further impaired the invasion and migration abilities of trophoblast cells. Injecting itaconate into pregnant mice increased the embryo resorption rate in mice. Exploring the mechanism of itaconate's action revealed that PI3K did not directly interact with itaconate. Itaconate might regulate the signal transduction by alkylating cysteine residues of upstream proteins such as IL21R or Oncostatin M receptor. Our research revealed the possible role of Acod1/Itaconate in RSA, and it may become a target for future intervention and treatment.

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ACOD1/Itaconate通过PI3K/Akt/FOLR1轴调控滋养细胞功能参与复发性自然流产的发病机制。

复发性自然流产（RSA）的发病机制尚不清楚。我们的研究重点是Aconitate decarboxylase 1 (Acod1)，并发现其在RSA中的作用。Western blotting、qPCR和免疫组化结果显示，Acod1在RSA患者的绒毛组织中明显上调。一方面，过表达Acod1抑制滋养细胞的侵袭和迁移能力。筛选细胞迁移相关差异表达基因，发现Acod1过表达后叶酸受体1 （FOLR1）显著下调。过表达FOLR1可以恢复滋养细胞的侵袭和迁移能力。另一方面，当滋养层细胞与巨噬细胞共培养时，过表达Acod1的滋养层细胞促进巨噬细胞向M1表型极化。Acod1主要通过催化过量衣康酸（ITA）的产生发挥作用。进一步分析KEGG结果发现，PI3K/Akt是Acod1/Itaconate作用的主要机制。过表达Acod1或添加外源性衣康酸抑制PI3K和Akt的磷酸化。我们还发现，Acod1在蜕膜巨噬细胞中异常升高，过表达Acod1的巨噬细胞进一步损害了滋养细胞的侵袭和迁移能力。给妊娠小鼠注射衣康酸可提高小鼠胚胎吸收率。对衣康酸作用机制的探索表明，PI3K并不直接与衣康酸相互作用。衣康酸可能通过烷基化上游蛋白如IL21R或Oncostatin M受体的半胱氨酸残基来调节信号转导。我们的研究揭示了Acod1/Itaconate在RSA中的可能作用，它可能成为未来干预和治疗的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.