Journal of Shanghai Jiao Tong University (Medical Science) >

2025 , Vol. 45 >Issue 6: 693 - 704

DOI: https://doi.org/10.3969/j.issn.1674-8115.2025.06.004

Basic research

Phosphatidylethanolamine promotes macrophage senescence and liver injury by activating endoplasmic reticulum stress

  • HAN Longchuan ,
  • LI Yue ,
  • ZOU Zhihui ,
  • LUO Jing ,
  • LI Ruoyi ,
  • ZHANG Yingting ,
  • TANG Xinxin ,
  • TIAN Lihong ,
  • LU Yuheng ,
  • HUANG Ying ,
  • HE Ming ,
  • FU Yinkun
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  • 1.Frontier Research Center for Cell Homeostasis and Disease Control; Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education; Department of Pathophysiology, Shanghai Jiao Tong University College of Basic Medical Sciences, Shanghai 200025, China
    2.Institute for Translational Medicine on Cell Fate and Disease, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
    3.Department of Pathology and Pathophysiology, School of Basic Medicine, Kunming Medical University, Kunming 650500, China
    4.Central Laboratory, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
First author contact:HAN Longchuan was primarily responsible for conducting experiments, organizing and analyzing data, and drafting and revising the manuscript. LI Yue contributed to experimental operations and manuscript revision. ZOU Zhihui and LUO Jing participated in data analysis and manuscript revisions. LI Ruoyi contributed to animal experiments and manuscript revisions. ZHANG Yingting, TANG Xinxin, TIAN Lihong, LU Yuheng and HUANG Ying participated in manuscript revisions. HE Ming and FU Yinkun were responsible for project design and manuscript revisions. All authors have read the final version of the paper and agreed to its submission.
FU Yinkun, E-mail: yinkunfu@shsmu.edu.cn
HE Ming, E-mail: heming@shsmu.edu.cn.

Received date: 2025-01-24

  Accepted date: 2025-02-28

  Online published: 2025-06-28

Supported by

National Natural Science Foundation of China(32371244);Eastern Talent Plan Leading Project;Innovative Research Team of High-Level Local Universities in Shanghai(SHSMU-ZDCX20212000);Youth Talent Support Program Project of the School of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine(2024RCZC-C-03)

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Abstract

Objective ·To investigate the effects and molecular mechanisms of phosphatidylethanolamine (PE) on macrophage senescence and its senescence-associated secretory phenotype (SASP), as well as its pathophysiological role in liver injury. Methods ·A macrophage senescence model was established using doxorubicin (DOX), followed by PE treatment. A mouse liver injury model was generated via intraperitoneal co-administration of PE and lipopolysaccharide (LPS) to investigate the effects of PE on liver injury. Senescence markers and SASP factors, including senescence-associated β-galactosidase (SA-β-gal), cell cycle inhibitor p21, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), were evaluated using SA-β-gal staining, quantitative real-time PCR, and Western blotting. RNA sequencing (RNA-seq) was performed, followed by Gene Ontology (GO) cellular component enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, Gene Set Variation Analysis (GSVA), and Gene Set Enrichment Analysis (GSEA), to explore the molecular mechanisms and signaling pathways by which PE promotes macrophage senescence. The expression of endoplasmic reticulum (ER) stress-related proteins, including inositol-requiring enzyme 1 α (IRE1α), spliced X-box binding protein 1 (XBP1s), activating transcription factor 6 (ATF6), ATF4, and C/EBP homologous protein (CHOP), was analyzed through in vivo and in vitro experiments. Results ·PE significantly promoted the expression of senescence markers SA-β-gal, p21, p16 and SASP factors. RNA-seq analysis revealed that ER stress was involved in PE-induced promotion of SASP. Further experiments demonstrated that PE activated the ER stress signaling pathway, promoting macrophage senescence and the expression of SASP factors. In vivo experiments further confirmed that PE exacerbated LPS-induced liver injury in mice through ER stress. Conclusion ·PE promotes macrophage senescence and the expression of SASP factors by activating ER stress signaling pathway, thereby aggravating LPS-induced liver injury.

Key words： phosphatidylethanolamine (PE); macrophage; senescence-associated secretory phenotype (SASP); liver injury; endoplasmic reticulum stress

Cite this article

HAN Longchuan , LI Yue , ZOU Zhihui , LUO Jing , LI Ruoyi , ZHANG Yingting , TANG Xinxin , TIAN Lihong , LU Yuheng , HUANG Ying , HE Ming , FU Yinkun . Phosphatidylethanolamine promotes macrophage senescence and liver injury by activating endoplasmic reticulum stress[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025 , 45(6) : 693 -704 . DOI: 10.3969/j.issn.1674-8115.2025.06.004

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