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

Abstract 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.