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

## TL;DR

This study shows how a metabolic enzyme called NNMT drives a cell transformation in scar tissue, leading to excessive scarring through epigenetic changes.

## Contribution

The study identifies NNMT as a metabolic-epigenetic regulator of macrophage-to-myofibroblast transition in hypertrophic scarring.

## Key findings

- NNMT depletion of NAD+ and SAM leads to epigenetic reprogramming and Prrx1 overexpression.
- Inhibiting NNMT disrupts myofibroblast formation and reduces scar volume in animal models.
- Macrophage-myofibroblast transition is a significant source of myofibroblasts in hypertrophic scars.

## 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.

In macrophage‐myofibroblast transition, upregulated NNMT depletes S‐Adenosylmethionine‌ (SAM) and nicotinamide adenine dinucleotide(NAD+), thereby triggering epigenetic reprogramming via Histone H3 Lysine 27 acetylation (H3K27ac) accumulation at the promoter region of master transcription factor Prrx1. This chromatin remodeling drives Prrx1 overexpression, enhancing its binding to super‐enhancers to activate a pro‐fibrotic transcriptional program that promotes myofibroblast lineage commitment and hypertrophic scar progression.