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.