{"title":"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。","authors":"Tingting Feng, Shujuan Wu, Jianye Fang, Jinli Ding, Fujin Shen, Jing Yang","doi":"10.1016/j.bcp.2025.117405","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117405"},"PeriodicalIF":5.6000,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"ACOD1/Itaconate regulates trophoblast function through the PI3K/Akt/FOLR1 axis to participate in the pathogenesis of recurrent spontaneous abortion.\",\"authors\":\"Tingting Feng, Shujuan Wu, Jianye Fang, Jinli Ding, Fujin Shen, Jing Yang\",\"doi\":\"10.1016/j.bcp.2025.117405\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":8806,\"journal\":{\"name\":\"Biochemical pharmacology\",\"volume\":\" \",\"pages\":\"117405\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2025-10-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biochemical pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.bcp.2025.117405\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochemical pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.bcp.2025.117405","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
ACOD1/Itaconate regulates trophoblast function through the PI3K/Akt/FOLR1 axis to participate in the pathogenesis of recurrent spontaneous abortion.
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.
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.
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