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

doi:10.3969/j.issn.1674-8115.2025.06.004

Abstract

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

CLC Number:

Q255

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.

Figures/Tables 6

TrendMD

References 31

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Gene	Forward primer (5′→3′)	Reverse primer (5′→3′)
p21	CCTGGTGATGTCCGACCTG	CCATGAGCGCATCGCAATC
p16	CCAGGGCCGTGTGCAT	TACGTGAACGTTGCCCATCA
Tnf-α	GCCACCACGCTCTTCTGTCTAC	GGGTCTGGGCCATAGAACTGAT
Il-6	GTTGTGCAATGGCAATTCTG	CTGGCTTTGTCTTTCTTGTTATCT
Il-1β	GCAACTGTTCCTGAACTCAACT	ATCTTTTGGGGTCCGTCAACT
Cxcl1	CTGCACCCAAACCGAAGTC	CCAGGGCCGTGTGCAT
Mmp13	CTTCTTCTTGTTGAGCTGGACTC	CTGTGGAGGTCACTGTAGACT
Ire1α	TCCTAACAACCTGCCCAAACA	AGATACGGTGGTCGGTGTGT
Atf6	GCAATACCTGTTCTTCCTCTGA	TCTAAACACCCACAAGCCACA
Chop	CCACCACACCTGAAAGCAGAA	AGGTGAAAGGCAGGGACTCA
β-actin	GGCTGTATTCCCCTCCATCG	CCAGTTGGTAACAATGCCATGT

Gene	Forward primer (5′→3′)	Reverse primer (5′→3′)
p21	CCTGGTGATGTCCGACCTG	CCATGAGCGCATCGCAATC
p16	CCAGGGCCGTGTGCAT	TACGTGAACGTTGCCCATCA
Tnf-α	GCCACCACGCTCTTCTGTCTAC	GGGTCTGGGCCATAGAACTGAT
Il-6	GTTGTGCAATGGCAATTCTG	CTGGCTTTGTCTTTCTTGTTATCT
Il-1β	GCAACTGTTCCTGAACTCAACT	ATCTTTTGGGGTCCGTCAACT
Cxcl1	CTGCACCCAAACCGAAGTC	CCAGGGCCGTGTGCAT
Mmp13	CTTCTTCTTGTTGAGCTGGACTC	CTGTGGAGGTCACTGTAGACT
Ire1α	TCCTAACAACCTGCCCAAACA	AGATACGGTGGTCGGTGTGT
Atf6	GCAATACCTGTTCTTCCTCTGA	TCTAAACACCCACAAGCCACA
Chop	CCACCACACCTGAAAGCAGAA	AGGTGAAAGGCAGGGACTCA
β-actin	GGCTGTATTCCCCTCCATCG	CCAGTTGGTAACAATGCCATGT