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代谢组学和蛋白质组学研究表明，抑制精氨酸琥珀酸合成酶1可缓解小鼠结肠炎。

Metabolomics and proteomics reveal blocking argininosuccinate synthetase 1 alleviates colitis in mice.

作者信息

Liu Shijia, Sun Haijian, Du Zijing, Lu Shuai, Wang Chenwen, Zhang Ye, Luo Zichen, Wang Lu, Fan Zhimin, Wei Peng, Yan Yujiao, Zhang Junzhi, Yin Shusheng, Liu Tongtong, He Qiongzi, Guo Xi, Ding Kang, Zhou Jingjie, Hua Haibing, Yu Chengli, Xu Weichen, Shan Jinjun, Li Yongming, Xu Yi, Shen Xiaotao, Cao Gang, Zhou Wei

机构信息

Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China.

Wuxi School of Medicine, Jiangnan University, Jiangsu, China.

出版信息

Nat Commun. 2025 Jul 30;16(1):6983. doi: 10.1038/s41467-025-62217-8.

DOI:10.1038/s41467-025-62217-8
PMID:40739098
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12311138/
Abstract

To date, treating ulcerative colitis (UC) remains a significant challenge due to its complex etiology. In this study, metabolomics and proteomics analysis for multi-center cohorts reveal that both serum arginine levels and the rate-limiting enzyme argininosuccinate synthetase 1 (ASS1) are significantly elevated in UC patients. Exogenous arginine infusion and ASS1 overexpression exacerbate the pathological features of colitis in mice, while inhibiting or silencing ASS1 offers protection against experimental colitis. The induction of ASS1 is accompanied by increased levels of acetylated H3 and trimethylated H3K4, along with decreased levels of dimethyl H3K9 around the ASS1 promoters, suggesting epigenetic activation of ASS1 in colitis. The ASS1/arginine axis triggers mTOR and iNOS activation and induces gut microbiota dysbiosis, leading to experimental colitis. Additionally, we identify a screened compound, C-01, which significantly improves colitis by highly binding to ASS1. Our findings suggest that ASS1 could be a promising target for UC treatment.

摘要

迄今为止，由于溃疡性结肠炎（UC）病因复杂，其治疗仍然是一项重大挑战。在本研究中，对多中心队列进行的代谢组学和蛋白质组学分析表明，UC患者的血清精氨酸水平和限速酶精氨琥珀酸合成酶1（ASS1）均显著升高。外源性精氨酸输注和ASS1过表达会加重小鼠结肠炎的病理特征，而抑制或沉默ASS1则对实验性结肠炎具有保护作用。ASS1的诱导伴随着H3乙酰化水平和H3K4三甲基化水平的增加，以及ASS1启动子周围H3K9二甲基化水平的降低，这表明结肠炎中ASS1存在表观遗传激活。ASS1/精氨酸轴触发mTOR和iNOS激活，并诱导肠道微生物群失调，从而导致实验性结肠炎。此外，我们鉴定出一种筛选化合物C-01，它通过与ASS1高度结合显著改善结肠炎。我们的研究结果表明，ASS1可能是UC治疗的一个有前景的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae03/12311138/fe7c13956b26/41467_2025_62217_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae03/12311138/8460be2368b5/41467_2025_62217_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae03/12311138/b53e26c267ef/41467_2025_62217_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae03/12311138/9fa989794c5f/41467_2025_62217_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae03/12311138/e38171009fab/41467_2025_62217_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae03/12311138/d3323fdee54b/41467_2025_62217_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae03/12311138/959b57d2b325/41467_2025_62217_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae03/12311138/fe7c13956b26/41467_2025_62217_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae03/12311138/8460be2368b5/41467_2025_62217_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae03/12311138/b53e26c267ef/41467_2025_62217_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae03/12311138/9fa989794c5f/41467_2025_62217_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae03/12311138/e38171009fab/41467_2025_62217_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae03/12311138/d3323fdee54b/41467_2025_62217_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae03/12311138/959b57d2b325/41467_2025_62217_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae03/12311138/fe7c13956b26/41467_2025_62217_Fig7_HTML.jpg

相似文献

[1]
Metabolomics and proteomics reveal blocking argininosuccinate synthetase 1 alleviates colitis in mice.

Nat Commun. 2025-7-30

[2]
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[5]
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[6]
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[8]
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[9]
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[10]
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本文引用的文献

[1]
Microbial metabolite deoxycholic acid-mediated ferroptosis exacerbates high-fat diet-induced colonic inflammation.

Mol Metab. 2024-6

[2]
Gut microbial metabolite deoxycholic acid facilitates Th17 differentiation through modulating cholesterol biosynthesis and participates in high-fat diet-associated colonic inflammation.

Cell Biosci. 2023-10-3

[3]
L-arginine metabolism as pivotal interface of mutual host-microbe interactions in the gut.

Gut Microbes. 2023

[4]
Illuminating the structure-function landscape of an evolutionary nonconserved motif in the arginases of Helicobacter gastric pathogens.

IUBMB Life. 2023-10

[5]
Human adipose tissue-derived small extracellular vesicles promote soft tissue repair through modulating M1-to-M2 polarization of macrophages.

Stem Cell Res Ther. 2023-4-7

[6]
IL-20 Activates ERK1/2 and Suppresses Splicing of X-Box Protein-1 in Intestinal Epithelial Cells but Does Not Improve Pathology in Acute or Chronic Models of Colitis.

Int J Mol Sci. 2022-12-22

[7]
Rewiring the altered tryptophan metabolism as a novel therapeutic strategy in inflammatory bowel diseases.

Gut. 2023-7

[8]
Arginine metabolism regulates the pathogenesis of inflammatory bowel disease.

Nutr Rev. 2023-4-11

[9]
massDatabase: utilities for the operation of the public compound and pathway database.

Bioinformatics. 2022-9-30

[10]
Lam. Peptide Remodels Intestinal Mucosal Barrier by Inhibiting JAK-STAT Activation and Modulating Gut Microbiota in Colitis.

Front Immunol. 2022

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