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

Abstract

Chronic inflammation drives the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) to fibrosis, yet how inflammatory signals establish profibrotic transcriptional states in hepatocytes remains poorly understood. Here, we identify nicotinamide N-methyltransferase (NNMT) as a previously unrecognized regulator linking inflammatory cytokine signaling to epigenetic and profibrotic responses in hepatocytes. NNMT was selectively induced by IL-1{beta} and IL-6, but not TNF, and its depletion markedly attenuated cytokine-induced inflammatory and fibrosis-associated transcriptional programs. IL-1{beta} activated NNMT through a JUN/AP-1-dependent pathway, whereas IL-6 sensitized IL-1{beta}-driven responses, an effect partially reversed by NNMT depletion. Integrative transcriptomic and epigenomic analyses revealed that NNMT-dependent gene regulation was associated predominantly with alterations in H3K27 acetylation (H3K27ac) rather than widespread changes in histone methylation. Notably, nicotinamide supplementation closely phenocopied NNMT depletion across cytokine-responsive H3K27ac regions, implicating nicotinamide-dependent regulation in the chromatin response. H3K27ac alterations were strongly concordant with inflammatory and fibrosis-associated transcriptional changes. These findings were further supported in primary human hepatocytes and three-dimensional human liver microtissues, where NNMT depletion reduced cytokine-induced procollagen secretion. Together, our findings identify an inflammation-NNMT-chromatin axis that couples inflammatory cytokine signaling to sustained profibrotic hepatocyte responses and highlight the drug-targetable enzyme NNMT as a potential therapeutic target for limiting MASLD progression and liver fibrosis.