2. Academic Validation
  3. NNMT/1-MNA protects against hepatic ischemia-reperfusion injury through the AKT/FOXO1/ANGPT2/JNK axis

NNMT/1-MNA protects against hepatic ischemia-reperfusion injury through the AKT/FOXO1/ANGPT2/JNK axis

  • Nat Commun. 2025 May 22;16(1):4779. doi: 10.1038/s41467-025-59968-9.
Bing Yin # 1 2,  Baolin Qian # 1 2,  Hongjun Yu # 1 2,  Shanjia Ke # 1 2,  Zihao Li 1 2,  Yongliang Hua 2 3,  Shounan Lu 1 2,  Chaoqun Wang 1 2,  Mengxin Li 4,  Sixun Guo 5,  Zhongyu Li 1 2,  Yongzhi Zhou 1 2,  Zhanzhi Meng 1 2,  Xinglong Li 1 2,  Yanan Xu 2 6,  Zhigang Feng 2 7,  Miaoyu Bai 1 2,  Yao Fu 8,  Wei Tang 9 10,  Shangyu Hong 11 12,  Yong Ma 13 14
Affiliations

Affiliations

  • 1 Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 2 Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.
  • 3 Department of Pediatric Surgery, the Sixth Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 4 State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
  • 5 Department of Pharmacy, The First affiliated Hospital of Harbin Medical University, Harbin, China.
  • 6 Department of Hepatopancreatobiliary Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 7 The First Department of General Surgery, The Affiliated Hospital of Inner Mongolia Minzu University, Tongliao, China.
  • 8 Department of Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 9 International Health Care Center, National Center for Global Health and Medicine, Tokyo, Japan.
  • 10 Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo Hospital, Tokyo, Japan.
  • 11 Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China. shangyu_hong@fudan.edu.cn.
  • 12 State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China. shangyu_hong@fudan.edu.cn.
  • 13 Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China. mayong@ems.hrbmu.edu.cn.
  • 14 Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China. mayong@ems.hrbmu.edu.cn.
  • # Contributed equally.
PMID: 40404636 DOI: 10.1038/s41467-025-59968-9
Abstract

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 N1-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.

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