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

Author

Listed:
  • Shijia Liu

    (Jiangsu Province Hospital of Chinese Medicine)

  • Haijian Sun

    (Jiangnan University)

  • Zijing Du

    (Nanyang Technological University
    Southern Medical University)

  • Shuai Lu

    (China Pharmaceutical University)

  • Chenwen Wang

    (China Pharmaceutical University)

  • Ye Zhang

    (China Pharmaceutical University)

  • Zichen Luo

    (Nanjing University of Chinese Medicine)

  • Lu Wang

    (Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine)

  • Zhimin Fan

    (Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine)

  • Peng Wei

    (Jiangsu Province Hospital of Chinese Medicine)

  • Yujiao Yan

    (Nanjing University of Chinese Medicine)

  • Junzhi Zhang

    (Jiangsu Province Hospital of Chinese Medicine)

  • Shusheng Yin

    (Nanjing University of Chinese Medicine)

  • Tongtong Liu

    (Jiangsu Province Hospital of Chinese Medicine)

  • Qiongzi He

    (Jiangsu Province Hospital of Chinese Medicine)

  • Xi Guo

    (China Pharmaceutical University)

  • Kang Ding

    (Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine)

  • Jingjie Zhou

    (The Affiliated Jiangyin Hospital of Nanjing University of Chinese Medicine)

  • Haibing Hua

    (The Affiliated Jiangyin Hospital of Nanjing University of Chinese Medicine)

  • Chengli Yu

    (Nanjing University of Chinese Medicine)

  • Weichen Xu

    (Nanjing University of Chinese Medicine)

  • Jinjun Shan

    (Nanjing University of Chinese Medicine)

  • Yongming Li

    (Nanjing University of Chinese Medicine)

  • Yi Xu

    (Jiangsu Province Hospital of Chinese Medicine)

  • Xiaotao Shen

    (Nanyang Technological University
    Nanyang Technological University)

  • Gang Cao

    (Zhejiang Chinese Medical University)

  • Wei Zhou

    (China Pharmaceutical University)

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.

Suggested Citation

  • Shijia Liu & Haijian Sun & Zijing Du & Shuai Lu & Chenwen Wang & Ye Zhang & Zichen Luo & Lu Wang & Zhimin Fan & Peng Wei & Yujiao Yan & Junzhi Zhang & Shusheng Yin & Tongtong Liu & Qiongzi He & Xi Guo, 2025. "Metabolomics and proteomics reveal blocking argininosuccinate synthetase 1 alleviates colitis in mice," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62217-8
    DOI: 10.1038/s41467-025-62217-8
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