Nature communicationsMay 22, 2025

NNMT and 1-MNA protect the liver from blood flow injury through a cell survival and stress response pathway

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Updated Apr 6, 2026

Abstract

A decrease in hepatic expression and serum 1-MNA levels is observed during .

Nicotinamide N-methyltransferase (NNMT) is involved in the conversion of nicotinamide to N-methylnicotinamide (1-MNA).
NNMT overexpression and treatment with exogenous 1-MNA may reduce the severity of hepatic ischemia-reperfusion injury (HIRI) in male mice and liver cell models.
NNMT and 1-MNA are associated with inflammation, cell death, and blood vessel damage during HIRI through the AKT/FOXO1//JNK signaling pathway.
Depleting NNMT in the liver is linked to increased levels of ANGPT2 and worsened HIRI, which can be improved by knocking down ANGPT2.
NNMT/1-MNA/ANGPT2 may play regulatory roles in HIRI through the JNK signaling pathway.

Simplified

Hepatic ischemia‒reperfusion injury () 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. (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//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. 1

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Competing interests: The authors declare no competing interests.

PubMed

NNMT and 1-MNA protect the liver from blood flow injury through a cell survival and stress response pathway

Abstract

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