ACADVL upregulation is associated with placental ferroptosis in intrahepatic cholestasis of pregnancy

IF 3.8 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids Pub Date : 2026-03-01 Epub Date: 2025-12-13 DOI:10.1016/j.bbalip.2025.159711

Mi Tang , Jianghui Cai , Ling Zhang , Liling xiong , Xuejia Gong , Jinzhu Fu , Peilin Wang , Mengqiu Luo , Hong Liu , Ying Ye , Min Yu , Heng Yu , ShaSha Xing , Xiao Yang

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引用次数: 0

Abstract

Introduction

Intrahepatic cholestasis of pregnancy (ICP) is a disorder characterized by maternal pruritus and elevated total bile acid concentrations during pregnancy, posing severe fetal risks associated with placental dysfunction. However, the mechanisms underlying ICP remain to be fully elucidated.

Methods

An integrated approach was employed, utilizing placental scRNA-seq, LC-MS/MS-based lipidomics, and public RNA-seq data. The AUCell package, PPI network analysis, Random Forest, Support Vector Machine, and LASSO regression analyses were utilized to explore mitochondrial functions and identify hub mitochondria-related genes (MRGs). KEGG, GSEA, and GSVA were employed to investigate potential biological mechanisms. Key findings were validated by immunohistochemistry, immunofluorescence, and western blotting. Reactive oxygen species (ROS), malondialdehyde (MDA) and transmission electron microscopy were utilized to evaluate oxidative stress levels, lipid peroxidation and conduct ultrastructural examinations of mitochondria, respectively.

Results

MRGs are primarily distributed in villous cytotrophoblast (VCT). KEGG analysis of VCT indicated a close association with oxidative phosphorylation, ROS, Lipid. ACADVL was identified as a hub MRG and was found increased in ICP placenta, particularly in VCT. Functional analysis of ACADVL^high VCT revealed enrichment in fatty acid metabolism and oxidative phosphorylation. Lipidomics identified substantial alterations in glycerophospholipid and glycerolipid metabolism, and polyunsaturated fatty acid (PUFA) metabolism pathways. Experimentally, we observed the mitochondrial ACADVL localization, increased DRP1, decreased MFN2 and GPX4, and increased ROS and MDA levels in ICP. Electron microscopy revealed ultrastructural features consistent with ferroptosis.

Conclusion

This study proposes a novel model linking ACADVL, lipid metabolism, mitochondrial dysfunction, and ferroptosis in ICP pathogenesis.

查看原文本刊更多论文

ACADVL上调与妊娠肝内胆汁淤积症患者胎盘铁下垂有关。

妊娠肝内胆汁淤积症（ICP）是一种以妊娠期间母体瘙痒和总胆汁酸浓度升高为特征的疾病，与胎盘功能障碍相关，对胎儿造成严重风险。然而，ICP的机制仍有待充分阐明。方法：采用综合方法，利用胎盘scRNA-seq、LC-MS/MS-based脂质组学和公开的RNA-seq数据。利用AUCell软件包、PPI网络分析、随机森林、支持向量机和LASSO回归分析来探索线粒体功能并鉴定中心线粒体相关基因（mrg）。使用KEGG、GSEA和GSVA来研究潜在的生物学机制。主要发现通过免疫组织化学、免疫荧光和免疫印迹进行验证。采用活性氧（ROS）、丙二醛（MDA）和透射电镜分别评价氧化应激水平、脂质过氧化和线粒体超微结构检查。结果：核磁共振成像主要分布于绒毛细胞滋养层（VCT）。KEGG分析显示VCT与氧化磷酸化、ROS、脂质密切相关。ACADVL被确定为枢纽MRG，并在ICP胎盘中发现增加，特别是在VCT中。ACADVLhigh VCT的功能分析显示脂肪酸代谢和氧化磷酸化富集。脂质组学鉴定了甘油磷脂和甘油脂代谢以及多不饱和脂肪酸（PUFA）代谢途径的实质性改变。实验中，我们观察到ICP线粒体ACADVL定位，DRP1升高，MFN2和GPX4降低，ROS和MDA水平升高。电镜显示超微结构特征与铁下垂一致。结论：本研究提出了一种将ACADVL、脂质代谢、线粒体功能障碍和铁下垂与ICP发病机制联系起来的新模型。

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

Biochimica et biophysica acta. Molecular and cell biology of lipids 生物-生化与分子生物学

CiteScore

11.00

自引率

2.10%

发文量

109

审稿时长

53 days

期刊介绍： BBA Molecular and Cell Biology of Lipids publishes papers on original research dealing with novel aspects of molecular genetics related to the lipidome, the biosynthesis of lipids, the role of lipids in cells and whole organisms, the regulation of lipid metabolism and function, and lipidomics in all organisms. Manuscripts should significantly advance the understanding of the molecular mechanisms underlying biological processes in which lipids are involved. Papers detailing novel methodology must report significant biochemical, molecular, or functional insight in the area of lipids.