# Lactate derived from macrophages drives skin dermal fibroblasts phenotypic remodeling via MCT1-primed histone H3 lysine 23 lactylation in hypertrophic scar

## TL;DR

This study shows that lactate from macrophages promotes scar formation by altering fibroblast behavior through a new molecular pathway involving histone lactylation.

## Contribution

The study reveals a novel mechanism where macrophage-derived lactate drives fibrosis via MCT1-mediated histone lactylation in fibroblasts.

## Key findings

- Macrophages in stiff environments are the main source of lactate in hypertrophic scars.
- Lactate through MCT1 increases H3K23la, activating profibrotic genes HEY2 and COL11A1.
- Blocking MCT1 reduces collagen buildup and scar formation in mice.

## Abstract

Hypertrophic scar (HS) is a fibroproliferative disorder characterized by fibroblast hyperactivation and aberrant extracellular matrix deposition. This study identifies macrophage-derived lactate as a key mediator of fibroblast phenotypic remodeling via monocarboxylate transporter 1 (MCT1)-mediated histone H3 lysine 23 lactylation (H3K23la) in HS. Elevated lactate levels and MCT1 expression were observed in HS tissues, with macrophages in stiff mechanical microenvironments identified as the primary lactate source. Lactate influx through MCT1 upregulated H3K23la, thereby promoting transcriptional activation of profibrotic genes HEY2 and COL11A1. Mechanistically, HEY2 activated YAP1/SMAD2 signaling, while COL11A1 stabilized MCT1 to enhance lactate transport, forming a positive loop that amplified fibrosis. Fibroblast-specific Mct1 deletion or pharmacological inhibition of Mct1 in male mice reduced collagen deposition, accelerated wound healing, and attenuated scar formation. Our findings redefine the macrophage-fibroblast crosstalk in HS and establish the MCT1-H3K23la-HEY2/COL11A1 axis, particularly its self-reinforcing loop, as a novel therapeutic target.

The study identified macrophage-derived lactate as a driver of hypertrophic scar. Lactate influx via MCT1 triggers histone lactylation in fibroblasts to activate profibrotic genes.