Tributyl phosphate induces liver aging via fumarate-mediated mitochondrial DNA escape triggered FPR2 activation

IF 6.6 2区环境科学与生态学 Q1 ENVIRONMENTAL SCIENCES

Ecotoxicology and Environmental Safety Pub Date : 2026-10-15 Epub Date: 2026-10-09 DOI:10.1016/j.ecoenv.2026.120885

Liwei Yang, Honghao Qian, Zhili Ge, Tianyou Wang, Jiaxin Zhang, Jingjing Shi, Huibin Jiang, Xinyu Zhang, Yuebin Lv, Liting Zhou

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引用次数: 0

Abstract

Background

Liver aging–induced failure and dysfunction in other organs constitute a critical aging phenotype that is distinct from chronological aging. Unlike intrinsic aging, hepatic senescence is predominantly driven by environmental factors. Tributyl phosphate (TBP) was identified as a potential key environmental trigger of liver aging; however, the underlying mechanisms remain largely elusive.

Methods

Rats and BRL-3A cells were treated with TBP. Serum metabolomics, liver proteomics, hepatocyte ultrastructure, β-galactosidase (β-GAL) activity, cell cycle progression, ROS and senescence-associated secretory phenotype (SASP) levels, as well as protein related to chromatin remodeling and DNA damage were used to evaluate liver aging. WRW4, ethidium bromide (EB), Lv-FH and monomethyl fumarate were utilized respectively to establish models of FPR2 inhibition, cytoplasmic mitochondrial DNA (mtDNA) depletion. fumarate clearance and supplied supplementation.

Results

TBP induced cell cycle arrest, increased β-GAL activity, and elevated ROS and MMP-1 levels while upregulating p53, lys9, and γ-H2A.X protein expression. Additionally, TBP inhibited HP1 protein expression in rat livers and cells(P < 0.05). Significant changes in metabolites and proteins following TBP exposure were enriched in aging-related pathways. After treating with, WRW4, EB, Lv/sh-FH and monomethyl fumarate respectively, these changes were all reversed in BRL-3A cells (P < 0.05).

Conclusion

This study elucidat the effect of fumarate-mediated mtDNA escape in liver aging induced by TBP. We found that exposure to TBP induces the levels of fumarate, which directly drives mtDNA escape and activates the FPR2, finally triggers liver aging of rats.

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磷酸三丁酯通过富马酸介导的线粒体DNA逃逸触发FPR2激活诱导肝脏衰老。

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来源期刊

Ecotoxicology and Environmental Safety 环境科学-毒理学

CiteScore

12.10

自引率

5.90%

发文量

1234

审稿时长

88 days

期刊介绍： Ecotoxicology and Environmental Safety is a multi-disciplinary journal that focuses on understanding the exposure and effects of environmental contamination on organisms including human health. The scope of the journal covers three main themes. The topics within these themes, indicated below, include (but are not limited to) the following: Ecotoxicology、Environmental Chemistry、Environmental Safety etc.