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-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.