Nicotinamide N-methyltransferase couples inflammation and epigenetic remodelling to hepatic fibrosis

Authors

Sukhanava, S., Valina Allo, P., He, Y., Chen, L., Zhu, Y., Youhanna, S., Garcia Irigoyen, O., Li, Q., Ellis, E., Lauschke, V. M., Treuter, E., Fan, R.

Abstract

Chronic inflammation is a key driver of progression from benign steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. The molecular mechanisms coupling inflammatory cytokine signaling to altered hepatocyte remodeling remain incompletely understood. Here, we report that nicotinamide N-methyltransferase (NNMT) is induced by specific inflammatory cytokines in hepatocytes and acts as a key hub to connect inflammation with fibrotic liver remodeling. Transcriptomic profiling of primary human hepatocytes and human hepatoma cell lines identified NNMT as a selective downstream target of IL-1b and IL-6, but not of TNFa. Genetic silencing of NNMT markedly attenuated cytokine-induced inflammatory and fibrotic gene expression programs and partially reversed IL-6-mediated sensitization of IL-1b responses. Integration of RNA-seq with ChIP-seq, CUTTag, and ATAC-seq revealed that inflammatory cytokines remodel the hepatocyte epigenome through coordinated changes in histone modifications. NNMT overexpression promoted selective remodeling of H3K4me2 chromatin landscapes, accompanied by activation of fibrosis-associated transcriptional programs. Nicotinamide supplementation partially suppressed inflammatory gene expression, supporting a role of NNMT-dependent NAD+ metabolism in this process. Importantly, cytokine-induced NNMT expression and its associated transcriptional program were conserved in primary human hepatocytes and 3D liver microtissues. We therefore conclude that NNMT functions as an inflammatory cytokine-inducible metabolic epigenetic integrator that links IL-1b and IL-6 signaling to chromatin remodeling and inflammatory transcriptional reprogramming in hepatocytes. These findings identify NNMT as a key regulator of inflammatory and profibrotic responses during MASLD progression and highlight NNMT as a potential therapeutic target for limiting liver inflammation and fibrosis.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 31 Jul 2026.

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