Yin Bing, Qian Baolin, Yu Hongjun, Ke Shanjia, Li Zihao, Hua Yongliang, Lu Shounan, Wang Chaoqun, Li Mengxin, Guo Sixun, Li Zhongyu, Zhou Yongzhi, Meng Zhanzhi, Li Xinglong, Xu Yanan, Feng Zhigang, Bai Miaoyu, Fu Yao, Tang Wei, Hong Shangyu, Ma Yong
Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.
Nat Commun. 2025 May 22;16(1):4779. doi: 10.1038/s41467-025-59968-9.
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-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.
肝缺血再灌注损伤（HIRI）发生于肝脏手术过程中，会导致诸如肝衰竭、住院时间延长以及发病率和死亡率增加等术后并发症。然而，HIRI的潜在机制仍不清楚。烟酰胺N-甲基转移酶（NNMT）促进烟酰胺转化为N-甲基烟酰胺（1-MNA），并在各种病理生理过程中发挥关键作用。在本研究中，我们发现在HIRI期间肝脏NNMT表达和血清1-MNA水平降低。NNMT过表达和外源性1-MNA处理均可减轻雄性小鼠HIRI模型和原代肝细胞H/R模型中的HIRI。从机制上讲，NNMT/1-MNA通过AKT/FOXO1/ANGPT2/JNK轴在HIRI期间的炎症、凋亡和血管损伤中起关键作用。肝脏特异性敲除NNMT会导致ANGPT2表达增加并加重HIRI，而ANGPT2敲低可减轻这些影响。我们的研究结果表明，NNMT/1-MNA/ANGPT2可能通过JNK信号通路调节HIRI。总之，我们阐述了NNMT在肝损伤中的功能及其潜在机制，为解决HIRI提供了潜在的新治疗策略。
