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

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background &amp; aims</jats:title> <jats:p> 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 <jats:italic>N</jats:italic> -methyltransferase (NNMT) is induced by specific inflammatory cytokines in hepatocytes and acts as a key hub to connect inflammation with fibrotic liver remodeling. </jats:p> </jats:sec> <jats:sec> <jats:title>Approach &amp; results</jats:title> <jats:p>Transcriptomic profiling of primary human hepatocytes and human hepatoma cell lines identified NNMT as a selective downstream target of IL-1β and IL-6, but not of TNFα. Genetic silencing of NNMT markedly attenuated cytokine-induced inflammatory and fibrotic gene expression programs and partially reversed IL-6-mediated sensitization of IL-1β responses. Integration of RNA-seq with ChIP-seq, CUT&amp;Tag, 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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>NNMT functions as an inflammatory cytokine-inducible metabolic– epigenetic integrator that links IL-1β 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.</jats:p> </jats:sec> <jats:sec> <jats:title>Impact and Implications</jats:title> <jats:p>This study identifies NNMT as a previously unrecognized metabolic–epigenetic integrator that selectively links IL-1β and IL-6 signaling to chromatin remodeling and inflammatory transcriptional reprogramming in hepatocytes. Our findings establish a non-canonical mechanistic framework by which inflammatory cytokines drive profibrotic gene expression during MASLD progression through. By uncovering NNMT as a critical mediator of inflammatory–epigenetic crosstalk, this work broadens our understanding of hepatocyte-intrinsic mechanisms underlying liver fibrosis and highlights NNMT as a promising therapeutic target for preventing the transition from steatosis to progressive MASH and fibrosis.</jats:p> </jats:sec> <jats:sec> <jats:title>Highlights</jats:title> <jats:list list-type="bullet"> <jats:list-item> <jats:p>NNMT is selectively induced by IL-1β and IL-6 in hepatocytes.</jats:p> </jats:list-item> <jats:list-item> <jats:p>NNMT controls fibrogenic gene expression modules.</jats:p> </jats:list-item> <jats:list-item> <jats:p>IL-6 amplifies IL-1β responses through an NNMT-dependent mechanism.</jats:p> </jats:list-item> <jats:list-item> <jats:p>NNMT links inflammatory signaling to epigenetic remodeling in MASLD.</jats:p> </jats:list-item> </jats:list> </jats:sec>