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

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, Kang Ding, Jingjie Zhou, Haibing Hua, Chengli Yu, Weichen Xu, Jinjun Shan, Yongming Li, Yi Xu, Xiaotao Shen (), Gang Cao () and Wei Zhou ()
Additional contact information
Shijia Liu: Jiangsu Province Hospital of Chinese Medicine
Haijian Sun: Jiangnan University
Zijing Du: Nanyang Technological 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
Gang Cao: Zhejiang Chinese Medical University
Wei Zhou: China Pharmaceutical University

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62217-8

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