Progesterone receptor membrane component 1 accelerates liver fibrosis by interacting with transforming growth factor β receptor

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-09-29 DOI:10.1016/j.lfs.2025.124000

Moeka Mukae , Je-Won Ko , Hyo-Jung Kwun , In-Jeoung Baek , Sang R. Lee , Eui-Ju Hong

{"title":"Progesterone receptor membrane component 1 accelerates liver fibrosis by interacting with transforming growth factor β receptor","authors":"Moeka Mukae , Je-Won Ko , Hyo-Jung Kwun , In-Jeoung Baek , Sang R. Lee , Eui-Ju Hong","doi":"10.1016/j.lfs.2025.124000","DOIUrl":null,"url":null,"abstract":"<div><h3>Aims</h3><div>Transforming growth factor-beta (TGF-β) is a central driver of hepatic stellate cell (HSC) activation via SMAD signaling, ultimately contributing to liver fibrosis and cirrhosis. While progesterone receptor membrane component 1 (Pgrmc1), a non-canonical progesterone receptor, has been implicated in liver metabolism, its role in liver fibrosis remains poorly understood.</div></div><div><h3>Main methods</h3><div>To investigate the involvement of PGRMC1 in liver fibrosis, we analyzed public Gene Expression Omnibus (GEO) datasets from cirrhotic patients. A carbon tetrachloride (CCl₄)-induced liver fibrosis model was established in wild-type and Pgrmc1-knockout (KO) mice. Additionally, primary hepatocytes and Lx-2 cells were used to explore cell-type specific signaling pathways.</div></div><div><h3>Key findings</h3><div>Public dataset analysis revealed that higher PGRMC1 expression is associated with cirrhosis development and shorter survival in cirrhotic patients. In a CCl₄-induced model, Pgrmc1-KO mice exhibited significant resistance to liver fibrosis with suppression of TGF-β signaling. However, Pgrmc1-KO primary hepatocytes were prone to CCl₄-induced apoptosis. Instead, PGRMC1 knockdown significantly reduced TGF-β receptor (TGF-βR) protein levels and SMAD phosphorylation. Inhibition of TGF-βR1 abrogated the reduction in SMAD phosphorylation observed in PGRMC1-knockdown cells and co-immunoprecipitation assay revealed the interaction between PGRMC1 and TGF-βR.</div></div><div><h3>Significance</h3><div>Collectively, our findings demonstrate that PGRMC1 plays a crucial role in liver fibrosis progression by regulating TGF-βR, highlighting its potential as a promising therapeutic target for antibody-based treatment.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"381 ","pages":"Article 124000"},"PeriodicalIF":5.1000,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Life sciences","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0024320525006368","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}

引用次数: 0

Abstract

Aims

Transforming growth factor-beta (TGF-β) is a central driver of hepatic stellate cell (HSC) activation via SMAD signaling, ultimately contributing to liver fibrosis and cirrhosis. While progesterone receptor membrane component 1 (Pgrmc1), a non-canonical progesterone receptor, has been implicated in liver metabolism, its role in liver fibrosis remains poorly understood.

Main methods

To investigate the involvement of PGRMC1 in liver fibrosis, we analyzed public Gene Expression Omnibus (GEO) datasets from cirrhotic patients. A carbon tetrachloride (CCl₄)-induced liver fibrosis model was established in wild-type and Pgrmc1-knockout (KO) mice. Additionally, primary hepatocytes and Lx-2 cells were used to explore cell-type specific signaling pathways.

Key findings

Public dataset analysis revealed that higher PGRMC1 expression is associated with cirrhosis development and shorter survival in cirrhotic patients. In a CCl₄-induced model, Pgrmc1-KO mice exhibited significant resistance to liver fibrosis with suppression of TGF-β signaling. However, Pgrmc1-KO primary hepatocytes were prone to CCl₄-induced apoptosis. Instead, PGRMC1 knockdown significantly reduced TGF-β receptor (TGF-βR) protein levels and SMAD phosphorylation. Inhibition of TGF-βR1 abrogated the reduction in SMAD phosphorylation observed in PGRMC1-knockdown cells and co-immunoprecipitation assay revealed the interaction between PGRMC1 and TGF-βR.

Significance

Collectively, our findings demonstrate that PGRMC1 plays a crucial role in liver fibrosis progression by regulating TGF-βR, highlighting its potential as a promising therapeutic target for antibody-based treatment.

查看原文本刊更多论文

黄体酮受体膜组分1通过与转化生长因子β受体相互作用加速肝纤维化。

目的：转化生长因子-β (TGF-β)是通过SMAD信号激活肝星状细胞（HSC）的核心驱动因子，最终导致肝纤维化和肝硬化。虽然黄体酮受体膜组分1 （Pgrmc1）是一种非规范的黄体酮受体，与肝脏代谢有关，但其在肝纤维化中的作用仍知之甚少。为了研究PGRMC1在肝纤维化中的作用，我们分析了来自肝硬化患者的公开基因表达综合（GEO）数据集。建立了四氯化碳（CCl₄）诱导的野生型和pgrmc1敲除（KO）小鼠肝纤维化模型。此外，原代肝细胞和Lx-2细胞用于探索细胞类型特异性信号通路。关键发现：公共数据集分析显示，PGRMC1的高表达与肝硬化患者的肝硬化发展和较短的生存期相关。在CCl - 4诱导的模型中，Pgrmc1-KO小鼠通过抑制TGF-β信号传导表现出明显的肝纤维化抗性。然而，Pgrmc1-KO原代肝细胞容易发生CCl₄诱导的凋亡。相反，PGRMC1敲低显著降低TGF-β受体（TGF-β r）蛋白水平和SMAD磷酸化。抑制TGF-βR1消除了PGRMC1敲除细胞中SMAD磷酸化的降低，共免疫沉淀实验揭示了PGRMC1与TGF-βR之间的相互作用。意义：总的来说，我们的研究结果表明PGRMC1通过调节TGF-βR在肝纤维化进展中起着至关重要的作用，突出了其作为基于抗体治疗的有希望的治疗靶点的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.