In a groundbreaking study published in Nature Communications, researchers have unveiled an intricate molecular pathway by which the NNMT/1-MNA axis confers remarkable protection against hepatic ischemia-reperfusion injury (IRI), a critical condition with significant clinical consequences. This discovery not only deepens our understanding of liver pathophysiology but also opens new therapeutic avenues that target key signaling networks to mitigate damage associated with ischemia and reperfusion, phenomena commonly occurring during liver surgeries and transplantation.
Hepatic ischemia-reperfusion injury is an inevitable yet complex pathologic process triggered by the temporary deprivation of blood supply followed by restoration, resulting in cellular stress, inflammation, and apoptosis. For decades, clinicians and scientists alike have wrestled with the challenge of reducing IRI’s detrimental impact on hepatic function and patient outcomes. The new findings focus on the nicotinamide N-methyltransferase (NNMT) enzyme and its metabolic product, 1-methylnicotinamide (1-MNA), which have historically been studied in cancer metabolism and inflammation but whose precise role in liver injury remained obscure until now.
The authors, led by Yin, Qian, and Yu, demonstrated that enhancing NNMT activity dramatically increased the levels of 1-MNA within hepatocytes exposed to ischemic conditions. This elevation proved essential in antagonizing apoptotic pathways and supporting cellular survival during reperfusion. Mechanistically, the study revealed a cascade involving the activation of the AKT kinase, phosphorylation and nuclear exclusion of the forkhead box O1 (FOXO1) transcription factor, suppression of angiopoietin 2 (ANGPT2) expression, and subsequent modulation of the c-Jun N-terminal kinase (JNK) pathway. Together, these molecular events orchestrate a concerted defense against oxidative stress and inflammatory signaling that typically drive tissue injury.
The research team utilized state-of-the-art genetic, pharmacological, and biochemical approaches to dissect this signaling axis. Employing in vivo murine models of hepatic IRI, they administered NNMT activators and 1-MNA supplementation, observing significant reductions in serum transaminases, histological liver damage, and inflammatory cytokine levels compared to controls. Conversely, silencing NNMT gene expression amplified liver injury, underscoring the enzyme’s protective role. These results were further corroborated by in vitro experiments on primary hepatocytes and hepatic stellate cells, which confirmed the mechanistic involvement of the AKT/FOXO1/ANGPT2/JNK pathway.
One transformative aspect of this work is the elucidation of how metabolic enzymes like NNMT, traditionally regarded for their roles in cellular metabolism, intersect with critical signaling pathways governing stress responses in non-neoplastic tissues. The modulation of FOXO1, a pivotal transcription factor implicated in gluconeogenesis, cell cycle regulation, and apoptosis, points to a finely tuned balance between metabolic adaptation and cell fate decisions in ischemic liver injury. By reducing ANGPT2, a molecule known to promote vascular instability and inflammation, the study reveals a novel anti-inflammatory mechanism linked to NNMT activity.
The JNK pathway’s involvement in hepatocyte apoptosis and inflammation has been extensively studied and associated with poor outcomes in IRI; thus, the discovery that the NNMT/1-MNA axis indirectly inhibits JNK activation via upstream signaling modifications offers a promising target for therapeutic intervention. This axis represents a multi-tiered checkpoint where metabolic signals intersect with transcriptional and post-translational regulators to halt progression toward cell death.
The potential clinical implications of these discoveries are vast. Current strategies to prevent hepatic IRI largely rely on supportive care and nonspecific pharmacological agents with limited efficacy. The identification of NNMT and 1-MNA as endogenous protective factors provides a tangible target for drug development. Small molecule NNMT activators or analogs of 1-MNA could be administered perioperatively to reinforce hepatic resilience during surgical interventions, markedly improving organ viability and patient prognosis.
Furthermore, this research paves the way for personalized medicine approaches. Variations in NNMT expression or function, potentially influenced by genetic polymorphisms or comorbid conditions such as metabolic syndrome, might predispose individuals to more severe IRI. Screening for such biomarkers could guide stratification of patients and tailored prophylactic therapies, enhancing the safety of hepatic surgeries and transplantation.
Delving deeper into the molecular mechanisms, the study highlights how AKT phosphorylation acts as a molecular switch promoting hepatocyte survival. AKT’s activation leads to phosphorylation of FOXO1, excluding it from the nucleus and preventing the transcription of genes involved in oxidative stress and apoptosis. This regulatory step also diminishes the expression of ANGPT2, thereby reducing endothelial dysfunction and inflammation within the liver microenvironment. The resultant decreased activation of JNK alleviates the pro-apoptotic signaling cascade, sparing hepatic cells from irreversible damage.
The researchers underscore the importance of crosstalk between hepatocytes and vascular endothelium in the context of IRI. By modulating angiopoietin signaling, NNMT/1-MNA not only protects parenchymal cells but also stabilizes the hepatic vasculature, reducing leukocyte infiltration and microvascular occlusion. This dual action is critical for preserving liver architecture and ensuring adequate post-ischemic perfusion.
Beyond liver-specific implications, the NNMT/1-MNA axis may represent a broader paradigm in ischemia-reperfusion biology. Similar protective effects mediated by this pathway could exist in other organs susceptible to ischemia, such as the heart, kidneys, and brain. Hence, the translational potential of targeting NNMT extends beyond hepatology, inviting cross-disciplinary collaboration in developing anti-IRI therapies.
The publication also raises intriguing questions about the metabolic adaptations during ischemia and recovery. NNMT’s role in methylation and nicotinamide metabolism intersects with cellular NAD+ pools and epigenetic regulation, suggesting that enhancing NNMT activity could influence redox homeostasis and gene expression dynamics during injury. Future studies exploring these connections will expand our understanding of metabolic control in tissue repair.
In summary, Yin and colleagues have mapped a sophisticated molecular network through which NNMT and its product 1-MNA guard the liver against ischemia-reperfusion injury. By activating AKT signaling, repressing FOXO1 and ANGPT2, and attenuating JNK-mediated apoptosis, this axis orchestrates a multifaceted protective response. The translational implications are profound, offering novel strategies to mitigate one of the greatest challenges in hepatic surgery and transplantation medicine.
As the quest for effective IRI therapeutics continues, targeting endogenous metabolic-signal transduction nodes like the NNMT/1-MNA axis holds immense promise. This pioneering study marks a significant step forward in hepatic injury research, harmonizing metabolic regulation with intricate signaling pathways to discern potential therapeutic targets. With further validation and drug development, it could soon transform clinical approaches, minimizing liver damage, improving graft survival, and enhancing quality of life for patients undergoing complex hepatic procedures.
Subject of Research: The protective role of NNMT and its metabolic product 1-MNA in hepatic ischemia-reperfusion injury mediated via the AKT/FOXO1/ANGPT2/JNK signaling axis.
Article Title: NNMT/1-MNA protects against hepatic ischemia-reperfusion injury through the AKT/FOXO1/ANGPT2/JNK axis.
Article References:
Yin, B., Qian, B., Yu, H. et al. NNMT/1-MNA protects against hepatic ischemia-reperfusion injury through the AKT/FOXO1/ANGPT2/JNK axis. Nat Commun 16, 4779 (2025). https://doi.org/10.1038/s41467-025-59968-9
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