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

Background & aimsChronic 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. Approach & resultsTranscriptomic profiling of primary human hepatocytes and human hepatoma cell lines identified NNMT as a selective downstream target of IL-1{beta} and IL-6, but not of TNF. Genetic silencing of NNMT markedly attenuated cytokine-induced inflammatory and fibrotic gene expression programs and partially reversed IL-6-mediated sensitization of IL-1{beta} responses. Integration of RNA-seq with ChIP-seq, CUT&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. ConclusionsNNMT functions as an inflammatory cytokine-inducible metabolic- epigenetic integrator that links IL-1{beta} 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. Impact and ImplicationsThis study identifies NNMT as a previously unrecognized metabolic-epigenetic integrator that selectively links IL-1{beta} 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. HighlightsO_LINNMT is selectively induced by IL-1{beta} and IL-6 in hepatocytes. C_LIO_LINNMT controls fibrogenic gene expression modules. C_LIO_LIIL-6 amplifies IL-1{beta} responses through an NNMT-dependent mechanism. C_LIO_LINNMT links inflammatory signaling to epigenetic remodeling in MASLD. C_LI