NNMT Orchestrates Metabolic‐Epigenetic Reprogramming to Drive Macrophage‐Myofibroblast Transition in Hypertrophic Scarring

Hypertrophic scar (HS) is a cutaneous fibrotic disorder characterized by persistent myofibroblast activation and excessive extracellular matrix deposition. Elucidating the origin and characteristics of myofibroblasts remains a central focus in the field. This study identifies a novel subtype of scar myofibroblasts originating from macrophage-myofibroblast transition (MMT). MMT cells constitute a significant proportion of HS myofibroblasts and drive HS progression. Multi-omics analysis uncovered nicotinamide N-methyltransferase (NNMT) as a metabolic orchestrator of MMT. Liquid chromatograph mass spectrometer reveals NNMT-mediated depletion of nicotinamide adenine dinucleotide (NAD⁺) and S-adenosyl methionine(SAM), triggering H3K27ac accumulation and H3K27me3 loss. This epigenetic reprogramming facilitated the expression of master transcription factor paired-related homeobox 1 (Prrx1) and its nuclear co-condensation with super-enhancer (SE) components. Inhibition of NNMT disrupted Prrx1-SE interactions, suppressed MMT in vitro, and reduced scar volume in vivo. This study 1) identifies a new origin of scar-associated myofibroblasts, 2) establishes metabolite-guided epigenetic alteration as a regulator of myofibroblasts cellular plasticity, and 3) nominates NNMT as a therapeutic target for HS and related fibrotic disorders.