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

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

  • Biochem Pharmacol. 2025 Dec;242(Pt 3):117405. doi: 10.1016/j.bcp.2025.117405.
Tingting Feng 1,  Shujuan Wu 2,  Jianye Fang 3,  Jinli Ding 4,  Fujin Shen 5,  Jing Yang 6
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
  • 2 Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
  • 3 Center for Reproductive Medicine, Women and Children's Hospital Affiliated to Qingdao University, Qingdao, China.
  • 4 Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China. Electronic address: djl@whu.edu.cn.
  • 5 Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China. Electronic address: sfj296@163.com.
  • 6 Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China. Electronic address: dryangjing@whu.edu.cn.
PMID: 41047036 DOI: 10.1016/j.bcp.2025.117405
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.

Keywords

Acod1; FOLR1; Itaconate; PI3K; Recurrent spontaneous abortion.

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