NNMT/1-MNA protects against hepatic ischemia-reperfusion injury through the AKT/FOXO1/ANGPT2/JNK axis
Hepatic ischemia‒reperfusion injury (HIRI) occurs during liver surgery, contributing to postoperative complications such as liver failure, prolonged hospital stays, and increased morbidity and mortality rates. Yet, the mechanism underlying HIRI remains unclear. Nicotinamide N-methyltransferase (NNMT) facilitates the conversion of nicotinamide into N<sup>1</sup>-methylnicotinamide (1-MNA) and plays crucial roles in various pathophysiological processes. In this study, we find a decrease in hepatic NNMT expression and serum 1-MNA levels during HIRI. Both NNMT overexpression and exogenous 1-MNA treatment alleviate HIRI in male mice HIRI models and primary hepatocytes H/R models. Mechanistically, NNMT/1-MNA plays key roles in inflammation, apoptosis, and vascular injury during HIRI through the AKT/FOXO1/ANGPT2/JNK axis. Hepatic-specific depletion of NNMT leads to increased ANGPT2 expression and exacerbates HIRI, effects that can be mitigated by ANGPT2 knockdown. Our findings suggest that NNMT/1-MNA/ANGPT2 may regulate HIRI via the JNK signaling pathway. In summary, we present the function of NNMT and its underlying mechanism in liver injury, providing potential new therapeutical strategies for addressing HIRI.
Authors
- Miaoyu Bai (ORCID: https://orcid.org/0000-0002-0467-4710)
- Hongjun Yu (ORCID: https://orcid.org/0000-0001-6754-4801)
- Shounan Lu (ORCID: https://orcid.org/0000-0001-9569-3644)
- Zhanzhi Meng
- Yongzhi Zhou
- Wei Tang (ORCID: https://orcid.org/0000-0002-7089-4391)
- Yong Ma (ORCID: https://orcid.org/0000-0002-6508-508X)
- Shangyu Hong (ORCID: https://orcid.org/0000-0001-6144-5618)
- Sixun Guo
- Shanjia Ke
- Yanan Xu (ORCID: https://orcid.org/0000-0003-3582-8863)
- Bing Yin (ORCID: https://orcid.org/0000-0001-8668-9504)
- Mengxin Li (ORCID: https://orcid.org/0000-0002-5911-7241)
- Zhigang Feng (ORCID: https://orcid.org/0000-0002-3879-485X)
- Yongliang Hua
- Zihao Li (ORCID: https://orcid.org/0000-0002-4040-8188)
- Chaoqun Wang (ORCID: https://orcid.org/0000-0002-2210-4340)
- Zhongyu Li (ORCID: https://orcid.org/0000-0001-8505-2077)
- Xinglong Li (ORCID: https://orcid.org/0000-0003-1656-7370)
- Yao Fu
- Baolin Qian
Institutions
- Ministry of Education of the People's Republic of China (CN)
- Harbin Medical University (CN)
- Fudan University (CN)
- National Center for Global Health and Medicine (JP)
- Third Affiliated Hospital of Harbin Medical University (CN)
- University of Tokyo Hospital (JP)
- Second Affiliated Hospital of Harbin Medical University (CN)
- Affiliated Hangzhou First People's Hospital, Westlake University, School of Medicine (CN)
- First Affiliated Hospital of Harbin Medical University (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-22
- DOI
- https://doi.org/10.1038/s41467-025-59968-9
- Citations
- 7
- Primary Topic
- Organ Transplantation Techniques and Outcomes
- Type
- article
- Field-Weighted Citation Impact
- 14.04
Funders
- Harbin Medical University
- National Natural Science Foundation of China
- Natural Science Foundation of Heilongjiang Province